EP1268419A1 - Pyrrolidine derivatives useful as bax inhibitors - Google Patents

Pyrrolidine derivatives useful as bax inhibitors

Info

Publication number
EP1268419A1
EP1268419A1 EP01929439A EP01929439A EP1268419A1 EP 1268419 A1 EP1268419 A1 EP 1268419A1 EP 01929439 A EP01929439 A EP 01929439A EP 01929439 A EP01929439 A EP 01929439A EP 1268419 A1 EP1268419 A1 EP 1268419A1
Authority
EP
European Patent Office
Prior art keywords
methoxyimino
biphenyl
pyπolidinecarboxamide
carbonyl
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP01929439A
Other languages
German (de)
French (fr)
Other versions
EP1268419B1 (en
Inventor
Serge Halazy
Matthias Schwarz
Anna Quattropani
Russel Thomas
Anthony Baxter
Alexander Scheer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Serono SA
Original Assignee
Applied Research Systems ARS Holding NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Applied Research Systems ARS Holding NV filed Critical Applied Research Systems ARS Holding NV
Priority to EP01929439A priority Critical patent/EP1268419B1/en
Publication of EP1268419A1 publication Critical patent/EP1268419A1/en
Application granted granted Critical
Publication of EP1268419B1 publication Critical patent/EP1268419B1/en
Priority to CY20061101060T priority patent/CY1105519T1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention is related to pyrrolidine derivatives. Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula I are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor.
  • said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea.
  • the present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation.
  • Oxytocin is a peptide hormone and causes the contraction of the uterus of mammals during labor.
  • the corresponding Oxytocin receptor belongs to the family of G-protein-coupled receptors and is similar to V ⁇ a and V 2 vasopressin receptors.
  • OT receptors increase dramatically during the course of pregnancy.
  • the concentration of OT receptors has been shown to correlate with spontaneous uterine activity (M. Maggi et al. J. Clin.Endocrinol Metabol; 70; 1142, 1990).
  • Premature labor, though, and premature birth is undesired as it represents a major cause of perinatal morbidity and mortality.
  • the management of preterm labor represents a significant problem in the field of obstetrics.
  • oxytocm modulator e.g. blocker or antagonists would likely be more efficacious for treating prete m labor than current regimens.
  • oxytocin at term has only an effect on the uterus, such an oxytocin modulator would have only few or no side effect.
  • dysmenorrhea is characterised by cyclic pain associated with menses during ovulatory cycles. Said pain is believed to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium.
  • an oxytocin antagonost is belived more efficacious for treating dysmenorrhea than current regimens.
  • Oxytocin Some agents counteracting the action of Oxytocin (OT) are currently used in clinical stu-dies.
  • Such tocolytic agents i.e. uterine-relaxing agents
  • beta-2-adrenergic agonists include beta-2-adrenergic agonists, magnesium sulfate and ethanol.
  • the leading beta-2-adrenergic agonists is Ritodrine, which causes a number of cardiovascular and metabolic side effects, including tachycardia, increased renin secretion, hyperglycemia and reactive hypoglycemia in the infant.
  • beta- 32-adrenergic agonists including terbutaline and albuterol have side effcts similar to those of ritodrine.
  • Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired.
  • Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
  • Ci-C ⁇ -alkyl refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl).
  • Preferred aryl include phenyl, naphthyl, phenantrenyl and the like.
  • d-C ⁇ -alkyl aryl refers to Cj-C 6 -alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
  • Heteroaryl refers to a monocyclic heteromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group.
  • Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, l,3,4-oxadiazolyl,l,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3- dihydrojbenzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl,
  • C C ⁇ -alkyl heteroaryl refers to Ci-C ⁇ -alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(lH-indol-3-yl)ethyl and the like.
  • alkynyl refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • Acyl refers to the group -C(O)R where R includes "Q-Ce-alkyl”, “aryl”, “heteroaryl”, “Q- Ce-alkyl aryl” or “Ci-Oalkyl heteroaryl”.
  • Acyloxy refers to the group -OC(O)R where R includes "C C 6 -alkyl”, “aryl”, “heteroaryl”, “ -Ce-alkyl aryl” or "Q-C ⁇ -alkyl heteroaryl”.
  • Alkoxy refers to the group -O-R where R includes “CrC 6 -alkyl” or “aryl” or “heteroaryl” or "Ci- -alkyl aryl” or " -Co-alkyl heteroaryl”.
  • Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.
  • Alkoxycarbonyl refers to the group -C(O)OR where R includes "CrC ⁇ -alkyl” or “aryl” or “heteroaryl” or “d-C 6 -alkyl aryl” or "Q-Ce-alkyl heteroaryl”.
  • Aminocarbonyl refers to the group -C(O)NRR' where each R, R' includes independently hydrogen or Q-C . -alkyl or aryl or heteroaryl or "CrC 6 -alkyl aryl” or "Q-Ce-alkyl hetero- aryl”.
  • Acylamino refers to the group -NR(CO)R' where each R, R' is independently hydrogen or "Ci-C ⁇ -alkyP or "aryl” or “heteroaryl” or “d-C.-alkyl aryl” or "Q-C 6 -alkyl heteroaryl”.
  • Halogen refers to fluoro, chloro, bromo and iodo atoms.
  • “Sulfonyl” refers to group “-SO 2 -R” wherein R is selected from H, "aryl”, “heteroaryl”, “C C ⁇ -alkyl”, “d-Ce-alkyl” substituted with halogens e.g. an -SO 2 -CF 3 group, " -C ⁇ -alkyl aryl” or "Q-C 6 -alkyl heteroaryl”.
  • Sulfoxy refers to a group “-S(O)-R" wherein R is selected from H, “d-Ce-alkyl", “Q-C 6 - alkyl” substituted with halogens e.g. an -SO-CF 3 group, "aryl”, “heteroaryl” , “Q-Ce-alkyl aiyl” or “C C 6 -alkyl heteroaryl”.
  • Thioalkoxy refers to groups -S-R where R includes "d-C ⁇ -alkyl” or “aryl” or “heteroaryl” or "CrC ⁇ -alkyl aryl” or “CrC . -alkyl heteroaryl”.
  • Preferred thioalkoxy groups include thiomethoxy, thioethoxy, and the like.
  • substitution could also comprise situations where neighboring substituents have undergone ring closure, notably when viccinal functional substituents are involved, thus forming e.g. lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
  • “Pharmaceutically acceptable salts or complexes” refers to salts or complexes of the below- identified compounds of formula I that retain the desired biological activity. Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disul-fonic acid, and polygalacturonic acid.
  • Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quarternary ammonium salt of the formula -NR,R',R" + Z " , wherein R, R', R" is independently hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
  • “Pharmaceutically active derivative” refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
  • Enantiomeric excess refers to the products that are obtained by an asymmetric synthesis, i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded.
  • asymmetric synthesis i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded.
  • racemic products are usually obtained that do however also have the inventive set out activity as OT-R antagonists.
  • pyrrolidine derivatives according to formula I are suitable pharmaceutically active agents, by effectively modulating, in particular by effectively inhibiting the OT-R function and more specifically by antagonising the oxytocin receptor.
  • oxytocin receptor When the oxytocin receptor is bound by the compounds according to formula I, oxytocin is antagonised by being blocked from its receptor and is therefore unable to exert its biologic or pharmacological effects.
  • the compounds of the present invention are therefore in particular useful in the treatment and/or prevention of oxytocm-related disorders of mammals and in particular of humans. These disorders mediated by the oxytocin receptor, are primarily preterm labor and dysmenorrhea.
  • the compounds according to the present invention are those of formula I.
  • Said formula also comprises its geometrical isomers, its optically active forms as enantio- mers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof.
  • Preferred pharmaceutically acceptable salts of the compound I are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and para- toluenesulfonate salts.
  • X is selected from the group consisting of CR 6 R 7 , NOR 6 , NNR 6 R 7 .
  • Q is NR 10 , O or S; n is an integer selected of 0, 1 or 2, preferably 0. m is an integer selected of 0, 1, 2 or 3, preferably 0 or 1.
  • Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
  • R 1 is selected from the group comprising or consisting of unsubstituted or substituted CrC 6 - alkyl, unsubstituted or substituted C -C 6 -alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, acyl, unsubstituted or substituted Cj-C ⁇ -alkyl aryl, unsubstituted or substituted d-C ⁇ -alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl group.
  • R 2 , R 3 , R 4 and R 5 are independently selected from each other from the group consisting of hydrogen, halogen, Ci-Cg-
  • R 6 and R 7 are independently selected from the group comprising or consisting of hydrogen, unsubstituted or substituted C C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsub- stituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted saturated or xmsaturated 3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted Q-C ⁇ -alkyl aryl, unsubstituted or substituted CrC ⁇ -alkyl heteroaryl.
  • R 8 , R 9 and R 10 are independently selected from the group comprising or consisting of hydrogen, unsubstituted or substituted C]-C 6 alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl.
  • each pair R 6 , R 7 and/or R 8 , R 9 could form together with the N atom to which they are attached a 3-8 membered substituted or unsubstituted, saturated or unsaturated heterocyclic ring which may contain 1-2 further heteroatoms selected from N, S and O and which is optionally fused with an aryl, heteroaryl or 3-8 membered saturated or unsaturated cycloalkyl ring.
  • R 11 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted C ⁇ -C 6 -alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary or tertiary amino groups or quarternary ammonium moieties, unsub-stituted or substituted saturated or unsaturated 3-8-membered cycloalkyl.
  • Preferred heteroaryls are pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzo-thienyl, 2,1,3- benzothiadiazolyl, 2,1,3-benzoxadiazolyl, benzodioxolyl, indolyl, isoindolyl, 3H-in
  • the pyrrolidine derivatives according to the present invention carry a residue B 1 which is a fused heterocycle of the formula
  • Particularly preferred pyrrolidine derivatives are those compounds according to formula I wherein X is NOR 6 , and R 6 is selected from the group consisting of H, unsubstituted or substituted Ci-C ⁇ alkyl, xmsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3- 8-membered cycloalkyl, xmsubstituted or substituted d-C 6 -alkyl aryl, unsubstituted or substituted d-C ⁇ -alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl groups.
  • R is H, alkyl or acyl.
  • pyrrolidine derivatives are those compounds according to formula I wherem X is CHR 6 , and R 6 is selected from the group consisting of halogen, cyano, unsubstituted or substituted C 3 -C 6 alkyl, xmsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted d-C 6 -alkyl aryl, xmsubstituted or substituted d-C ⁇ -alkyl heteroary
  • R 1 are substituted or unsubstituted d-C ⁇ -alkyl, Q-Ce-alkenyl, xmsubstituted or substituted C -C 6 -alkynyl, aryl, heteroaryl, saturated or xmsaturated 3-8- membered cycloalkyl and still more preferred R 1 are CrC ⁇ -alkyl or aryl.
  • a particularly preferred substituent R 1 is biphenyl.
  • the compounds of formula I may contain one or more asymmetric centers and may therefore exist as enantiomers or diasteroisomers. It is to be understood that the invention inclu-des both mixtures and separate individual isomers or enantiomers of the compounds of formula I.
  • the pyrrolidine derivatives according to formula I are obtained in an enantiomeric excess of at least 52 % ee, preferably of at least 92-98% ee.
  • the most preferred compounds are those which are selected from the group consisting of:
  • a further aspect of the present invention is related to the use of the pyrrolidine derivatives according to formula I for the preparation of pharmaceutical compositions for the treatment and/or prevention of premature labor, premature birth, for stopping labor prior to cesarean delivery and dysmenorrhea.
  • the compounds according to formula I are suitable for the modulation of the OT function, thus specifically allowing the treatment and/or pre-vention of disorders which are mediated by the oxytocin receptor.
  • Said treatment involves the modulation - notably the down regulation or the antagonisation - of the oxytocin recep-tor.
  • the compounds of the present mvention are useful for the treatment of preterm labor, premature birth, dysmenorrhea and for stopping labor prior to cesarean delivery.
  • Still a further aspect of the present invention is related to the actually novel pyrrolidine compounds of formula I. Some very few compounds have actually been disclosed prior to the filing of the present application, without any medical use though. Said known corn-pounds of formula I are those, wherein
  • X is C 1 -C 20 alkylidene
  • R 1 is a t-butyl
  • B is
  • R is C ⁇ -C 12 alkyl and Hal is Cl, Br, J. Said compoxmds are disclosed in DE-1, 932,823 as intermediates.
  • X is C 1 -C 2 0 alkylidene
  • A-R 1 is a protective group
  • B is
  • R being H or d-C 12 alkyl (GB- 1,118,306)
  • novel compounds are those of the formula I, wherein the above mentioned known compounds are excluded.
  • Still a further object of the present invention is a process for preparing the pyrrolidine derivatives accordmg to formula I.
  • the pyrrolidine derivatives exemplified in this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the parti-cular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimisation procedures.
  • the pyrrolidine derivatives according to the general formula I could be obtained by several processes, using both solution-phase and solid-phase chemistry protocols. Depending on the nature of A, B, and X, certain processes will, in some instances, be preferred over others, and it is assumed that the choice of the most suitable process will be known to the practitioner skilled in the art.
  • pyrrolidine derivatives according to the general formula I whereby the substituent B is C(O)-NR 8 R 9 , with R 8 and R 9 being defined as above, are prepared from the corresponding suitably N-protected 4-substituted pyrrolidine derivatives II, whereby the substituent X is as above defined, by solution-phase chemistry protocols such as described in the Examples and shown in Scheme 1, below.
  • the suitably N-protec-ted 4-substituted pyrrolidine derivatives II are first reacted with primary or secondary amines III, whereby the substituents R and R are as above defined, using conditions and methods well known to those skilled in the art to prepare an amide from an amine and a carboxylic acid or a carboxylic acid derivative, using standard peptide coupling agents, such as e.g. DIC, EDC, TBTU, DECP, or others, to yield compounds of formula TV.
  • Re-moval of the N-protecting group using the appropriate deprotection agents produces deriva-tives of formula V.
  • These can be treated with acylating agents of general formula VI, whereby the substituent R 1 is as above defined, while LG could be any appropriate leaving group.
  • Preferred acylating agents VI are acid chlorides (Via), used in conjunction with a tertiary amine base, or carboxylic acids (Vlb), used in conjunction with a peptide coupling agent, e.g. from the above mentioned group, to yield the products of general formula I, with B being defined as C(O) ⁇ 8 R 9 (la).
  • Compoxmds of formula Xlla are commercially available or prepared by standard synthetic techniques as hereinafter described in the Examples.
  • pyrrolidine derivatives according to the general formula I whereby the substituent B is a heterocyclic residue Bl as above defined, and the substituents are as above defined, are prepared from the corresponding suitably N-protected 4-substituted pyrrolidine derivatives II, whereby the substituent X is as above defined, by solution-phase chemistry protocols such as described in the Examples and shown in Scheme 5, below.
  • N-protected 4-substituted pyrrolidine derivatives II are first reacted with ortho-substituted primary anilines of general formula XIII, whereby the substituents Q, Z, E, Y, and R 11 are as above defined, using standard peptide coupling agents, such as DIC, EDC, TBTU, DECP, or others, followed by exposure to dilute weak acid, such as acetic acid, in a suitable organic solvent, such as DCM, to promote cyclisation yielding compounds of formula XIV. Removal of the N-protecting group using the appropriate deprotection agents produces cyclic derivatives of formula XV.
  • acylating agents VI are acid chlorides (Via), used in conjunction with a tertiary amine base, or carboxylic acids (Vlb), used in conjunction with a peptide coupling agent, e.g. from the abovementioned group, to yield the products of general formula I, with B being defined as Bl (lb).
  • pyrrolidine derivatives according to the general formula I whereby the substituents A, B, X, and R are as above defined, are prepared from compounds of formula XVI, using the synthetic techniques as outlined in Schemes 2 and 4.
  • compounds of formula XVI are accessible either from XI, following, e.g., the synthetic methodologies introduced in Schemes 1 and 5, or from Ic through hydrolysis of the methyloxime moiety, e.g. under mild hydrolysis conditions as described hereinafter in the Examples.
  • This present synthetic strategy is most preferred when X is NOH or NNR 6 R 7 , whereby the substituents R 6 and R 7 are as above defined.
  • pyrrolidine derivatives according to the general formula I whereby the substituents A, B, X, and R 1 are as above defined, are prepared from the corresponding suitably N-protected 4-substituted pyrrolidine derivatives II, whereby the substituent X is above defined, by a solid-phase protocol such as described in the examples and shown in Scheme 7, below.
  • the N-Boc-protected 4-substituted pyrrolidine derivative II is reacted e.g.
  • acylating agents VI are acid chlorides (Via), used in conjxmction with a tertiary amine base, or carboxylic acids (Vlb), used in conjunction with a peptide coupling agent, e.g. DIC or EDC, to yield products of general formula XX.
  • Compoxmds of formula I wherem A is different from the carbonyl functionality are pre-pared by replacing formula VI with compounds containing the appropriate functional groups, e.g. sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, substituted alkyl halides, or others to yield sulfonamide, urea, thiourea, carbamate, substituted alkyl derivatives, or others respectively.
  • sulfonyl chlorides isocyanates, isothiocyanates, chloroformates, substituted alkyl halides, or others to yield sulfonamide, urea, thiourea, carbamate, substituted alkyl derivatives, or others respectively.
  • the linkage to the resin is cleaved by prolonged treatment with amines of general formulae III or XIII and low percentages of a weak acid, such as HOAc.
  • a weak acid such as HOAc.
  • the cycles within the below Scheme 7 illustrate the resign beads to which the corresponding compounds are linked during the solid phase synthesis.
  • Other derivatives of formula I are prepared using known modifications to, or variations of, the Scheme 7 reaction sequence.
  • suitable reagents notably resins, known to a person skilled in the art, could be employed for the solid-phase synthesis of compounds of general formula I.
  • compounds of formula I can be converted to alternative compoxmds of formula I, employing suitable interconversion techniques such as hereinafter described in the Examples.
  • Compoxmds ofthis mvention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent.
  • the pharmaceutically acceptable acid addition salts of the compoxmds of formula I which contain a basic center, may be prepared in a conventional manner.
  • a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of formula I with a suitable base. Both types of salt may be formed or interconverted using ion- exchange resin techniques.
  • a final aspect of the present invention is related to the use of the compounds according to formula I for the modulation of the Oxytocm receptor, the use of said compounds for the preparation of pharmaceutical compositions for the modulation of the oxytocin receptor as well as the formulations containing the active compoxmds according to formula I.
  • Said modulation of the oxytocin receptor is viewed as a suitable approach for the treatment of preterm labor, premature birth and dysmenorrhea.
  • the compoxmds od the present invention are suitable for the treatment of preterm labor, premature birth and dysmenorrhea.
  • the pyrrolidine derivatives of the present mvention are typically administered in the form of a pharmaceutical composition.
  • pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope of the present invention.
  • a person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition.
  • the present invention provides compounds for use as a medicament.
  • the invention provides the compounds of formula I for use as antagonists of the oxytocin receptor, for the treatment or prevention of disorders mediated by the oxytocin receptor in mammals, notably of humans, either alone or in combination with other medicaments, e.g. in combination with a further OT antagonist.
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use).
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pyrrolidine derivatives ofthis invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds ofthis invention are administered in a pharmaceutically effective amoimt.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of these inventions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compounds are preferably formulated as either injectable or oral compositions.
  • the compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for hximan subjects and other mammals, each unit containing a predeter-mined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the pyrrolidine compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatine
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the pyrrolidine derivatives of formula I in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • the compounds ofthis mvention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can also be found in the incorporated materials in Remington 's Pharmaceutical Sciences.
  • the 8N chromic acid solution (115ml) was then added dropwise over a period of 30 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of 25 °C by the use of an ice bath.
  • the reac-tion mixture was stirred for a further 15 minutes - maintaining the optimal temperature of 25 °C.
  • the reaction mixture was then quenched by the addition of methanol (20ml). Exotherm controlled by the use of an ice bath and, if necessary, direct addition of a small amount of crushed ice to the reaction mixture itself.
  • the reaction mixture was filtered through a Celite pad and then concentrated in vacuo.
  • Chloromethyltriphenylphosphonium iodide (270mg, 0.62mmol) was added to a solution of potassium tert-butoxide (67mg, 0.59mmol) in anhydrous diethyl ether (5ml) under nitrogen and the resulting bright yellow mixture stirred for 30 minutes at ambient temperature. The reaction was then cooled to 0°C and a solution of 1 -tert-butyl 2-methyl (2S)-4-oxo-l,2- pyrrolidinedicarboxylate (lOOmg, 0.41mmol in 2ml anhydrous diethyl ether) was added dropwise.
  • the reaction was then warmed to room temperature and stirred for 30 minutes before adding saturated aqueous ammonium chloride solution (0.5ml).
  • saturated aqueous ammonium chloride solution 0.5ml
  • the organic layer was removed in vacuo, and the aqueous washed with diethyl ether (3 x 5ml).
  • the combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent.
  • the desired product was isolated by silica gel chromatography, eluting with 15% ethyl acetate in hexanes to give 105mg (93% yield) as a off-white wax.
  • the acidic layer was then extracted with ethyl acetate (3 x 20ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo.
  • the desired product (5.3g, 94%) was isolated as a pale yellow oil.
  • the acidic layer was then extracted with ethyl acetate (3 x 20ml) and the combined organic layers washed with brine before drying over magnesium sulfate, filtering and re-moval of solvent in vacuo.
  • the desired product (5.9g, 94%) was isolated as a pale yellow oil.
  • Acetyl chloride (30ml, 0.42mol) was added and the reaction stirred for 6 hours at room temperature. The excess of acetyl chloride was removed in vacuo and the crude dissolved in DCM(lQOml). The organic layer was washed with water (50ml), brine and dried over magnesium sulfate before being concentrated ⁇ in vacuo. The desired product (1.86g, 77%) was isolated as a colourless oil and was used without further purification. A solution was made containing the O-acyl, Boc-ethanolamine (1.65g, ⁇ .lmmol) in DCM (20ml) and TFA (20ml) was added. After one hour at room temperature, the solvent was removed in vacuo. The crude was concentrated from methanol (2-3 times) and from DCM (2-3 times) to give the expected compound (1.75g, quant.) as an oil used without further purification.
  • 1,1' -biphenyl intermediates 13 may be obtained: 4'-methyl[l,l'-biphenyl]-4-carboxylic acid; 2',3-dimethyl[l,r-biphenyl]-4-carboxylic acid; 2',6'-dimethyl[l,r-biphenyl]-4-carboxylic acid; 2-methyl[l,l'-biphenyl]-4-carboxylic acid; 3- methyl[l,r-biphenyl]-4-carboxylic acid; 2,2'-dimethyl[l,r-biphenyl]-4-carboxylic acid; 2'- methoxy[l,r-biphenyl]-4-carboxylic acid; 3 '-methoxy [l,r-biphenyl]-4-carboxylic acid; 4'- methoxy[l,r-biphenyl]-4-carboxylic acid; 4'- methoxy[l,r-b
  • Example 1 General procedure for the saponification of the olefin-type proline methyl esters, such as Intermediates 3-6.
  • the DCM was evaporated and the crude purified by column chromatography using ⁇ tOAc (100%) to collect the desired product, e.g. tert-butyl (2S,4EZ)-2- ⁇ [(2-meth-oxyethyl)amino]carbonyl ⁇ -4- (methoxyimino)-l-py ⁇ olidmecarboxylate (1.5g, 80%) as a colourless oil.
  • desired product e.g. tert-butyl (2S,4EZ)-2- ⁇ [(2-meth-oxyethyl)amino]carbonyl ⁇ -4- (methoxyimino)-l-py ⁇ olidmecarboxylate (1.5g, 80%) as a colourless oil.
  • Protocol for the N-capping step A solution was made containing the free NH-compoxmd from the previous step, e.g. (2S,4EZ)- N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide (940mg, 3.7 mmol), a carboxylic acid, e.g. [l,l'-biphenyl]-4-carboxylic acid (740mg, 3.7mmol) and DMAP (960mg, 7.8mmol) in DCM (30 ml). At 0°C, ⁇ DC (715mg, 3.7mmol) was slowly added portionwise. The reaction was slowly allowed to reach room temperature and was stirred overnight.
  • 2S,4EZ N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
  • a carboxylic acid e.g. [l,l'-biphenyl]-4-carboxylic acid (7
  • Method B e.g. (2S.4E and 4Z)-N-r(2S)-2-hvdroxy-2- ⁇ >henylethyl]-4-(methoxyimino)-l-r(2'- methyl[ 1 , 1 '-biphenyl] -4-yl carbonyl1 -2-p yrrolidinecarboxamide
  • the pure E-isomer was isomerized to a mixture of the E/Z-isomers by the following procedure: the E-isomer was dissolved in dioxane/water 3:1 mixture. NaOH (1.7 eq; 0.52 mL of NaOH 1.6N) was added and the resultmg solution was sti ⁇ ed 2 h at r.t. The mixture was neutralised with HCl 0.1 N and lyophilised. The components of the resulting E/Z-mixture were separated and purified by flash chromatography using same conditions as described above.
  • Example 2 Following the general method as outlined in Example 2, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(chloromethylene)-2-py ⁇ olidinecarboxylic acid, [ 1,1' -biphenyl] -4- carboxylic acid, and (li?S)-2-amino-l-phenylethanol, the title compoxmd was obtained after column chromatography as a mixture of E/Z-isomers as an off-white solid. The two isomers could be separated by another flash chromatographic purification step.
  • Example 5 f2S.4EZ)-N-r2-fdiethylamino)ethyl]-l -(diphenylacetylV4-(metho ⁇ yimmoV2- py ⁇ olidinecarboxamide
  • (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-py ⁇ olidinecarboxylic acid, diphenylacetic acid, and ⁇ N 1 -diethyl- 1,2-ethanediamine the title compound was obtained after column chromatography as an off-white solid as amixture of ⁇ /Z-isomers.
  • Example 9 General protocol for the solution-phase synthesis of oximether pyrrolidine derivatives of general formula I containing additional reactive groups; (2SAEZ)- ⁇ -( ⁇ ,Y- biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl -4-rmethoxyimino -2-py ⁇ olidinecarboxamide
  • a solution was made containing the amine-hydrochloride from the previous step, e.g. 2- ( ⁇ [(2S,4EZ)-4-(methoxyimino)pyrrolidinyl]carbonyl ⁇ amino)ethyl acetate (560mg, 2mmol) and an acid chloride, e.g. [1,1 '-biphenyl] -4-carbonyl chloride (433mg, 2mmol) in DCM (20ml). Triethylamine (0.7ml, 5__ ⁇ mol) was added and the reaction sti ⁇ ed overnight at room temperature. The DCM was evaporated and the crude purified by column chromatography using EtOAc (100%) to collect the desired amide compound, e.g.
  • a solution was made containing the side-chain protected compound from the previous step, e.g. 2-( ⁇ [(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)py ⁇ olidinyl] carbo- nyl ⁇ amino)ethyl acetate (450mg, 10.6mmol) in THF (10ml). An aqueous solution (10ml) of sodium hydroxide (75mg, 19mmol) with methanol (5ml) was added and the reaction sti ⁇ ed at room temperature for three hours.
  • Example 11 General protocol for the solution-phase synthesis of oximether pyrrolidine derivatives of general formula lb (Scheme 5); (3EZ,5S)-5-(lH-benzimidazol-2-ylVl-([l,r- biphenyl]-4-ylcarbonyl -3-py ⁇ olidinone O-methyloxime
  • a solution was prepared containing the central building block, e.g. (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-py ⁇ olidinecarboxylic acid (Intermediate 7) (2.1g, ⁇ .lmmol), an ortho-substituted aromatic amine or amine salt, e.g. 1,2-benzenediamine (0.88g, ⁇ .lmmol) and DMAP (1.59g, 13.0mmol). in dry dichloromethane (30ml). This solution was cooled to 0°C and treated with ⁇ DC (1.56g, 8.2mmol) before warmmg to room temperature and stirring for 2 days.
  • 2S,4EZ 2-(tert- butoxycarbonyl)-4-(methoxyimino)-2-py ⁇ olidinecarboxylic acid
  • Intermediate 7 2.1g, ⁇ .lmmol
  • an ortho-substituted aromatic amine or amine salt e.g.
  • Hydrogen chloride gas was bubbled into a solution of the fused heterocyclic product from the previous step, e.g. tert-butyl (2S,4EZ)-2-(lH-benzimidazol-2-yl)-4-(methoxyimino)-l- py ⁇ olidinecarboxylate (740mg, 2.2mmol) in dry DCM (20ml) for 30 min..
  • the solvent was removed in vacuo to give the desired product, e.g. (3EZ,5S)-5-(lH-benzimidazol-2-yl)-3- py ⁇ olidinone O-methyloxime (0.58g, 99%), as a brown amorphous powder which was used without further purification.
  • Example 17 General protocol for the solution-phase synthesis of oxime or hydrazone py ⁇ olidine derivatives of general formula I (Scheme 6); (2S, 4EZ)-l-([l,l'-biphenyl]-4- ylcarbonyl)-4-(hvdroxyimino)-N-[(2i?S)-2-hydroxy-2-phenethyl]-2-py ⁇ olidine-carboxamide.
  • the starting oximether compounds e.g. (2S,4EZ)-l-([l,l*-bi ⁇ henyl]-4-ylcarbonyl)-N-[(2RS)- 2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-py ⁇ olidinecarboxamide, were obtained following the general methods as outlined, e.g., in Example 2, 11 or 22.
  • a solution containing the oximether compoxmd was prepared, e.g.
  • ketocarbonyl product e.g. (2S)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo- 2-py ⁇ olidmecarboxamide (56 mg, 92%) was isolated as a yellow oil and used without further purification.
  • the resultant crude reaction mixture was purified by column chromatography using DCM MeOH (25:1) to collect the desired product, e.g. (2S, 4EZ)-l-([l, -biphenyl]-4-ylcarbonyl)-4-(hydroxy-imino)- N-[(2RS)-2-hydroxy-2-phenethyl]-2-py ⁇ olidme-carboxamide as a mixture of two isomers as an off-white solid (46 mg, 96% yield).
  • desired product e.g. (2S, 4EZ)-l-([l, -biphenyl]-4-ylcarbonyl)-4-(hydroxy-imino)- N-[(2RS)-2-hydroxy-2-phenethyl]-2-py ⁇ olidme-carboxamide
  • Example 19 (2S.4EZ)-l-(ri.r-biphenyl]-4-ylcarbonyl -N-r(2RS)-2-hydroxy-2-phenylethyl]-4- (methylhydrazono -2-py ⁇ olidinecarboxamide
  • (2S)-1-([1,1'- biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-py ⁇ olidinecarbox- amide and N-methylhydrazine the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (30:1) to collect the desired product, e.g.
  • Example 21 (2S.4EZ)-4-(acetylhvdrazonoVl-([l J'-biphenyl1-4-ylcarbonyl -N-r(2J?S)-2- hydroxy-2-phenylethyl]-2-py ⁇ olidinecarboxamide
  • a hydrazono py ⁇ olidine derivative obtained by the general method outlined in Example 17, e.g.
  • Example 22 General protocol for the solid-phase synthesis of py ⁇ olidine derivatives of general formula I.
  • Kaiser oxime resin (16.5g, loading 1.57mmol/g) was added to a solution of the relevant py ⁇ olidine carboxylic acid building block (51.8mmol) and diisopropylcarbodiimide (8.1ml, 51.8mmol) in dry dichloromethane (150ml). The resulting suspension was shaken overnight before filtering at the pump and washing sequentially with DMF, DCM and finally diethyl ether before drying at room temperature in vacuo.
  • the resin from the previous step was transfe ⁇ ed into a 96-well filter-plate (approx. 50mg of dry resin/well) and each well treated with an N-reactive derivatising agent, e.g. with either of the following solutions:
  • the plate was then sealed and shaken overnight at ambient temperature.
  • the resins were then filtered, washing the resin sequentially with aliquots of DMF, DCM and finally diethyl ether before drying at room temperature in vacuo.
  • Example 42 tert-butyl 3- ( ⁇ (2S.4EZ)-4-(ethoxyimino -l-r(2-oxo-6-pentyl-2H-pyran-3- yl carbonyl]pyrrolidinyllcarbonyl amino1-l-azetidinecarboxylate
  • Example 47 l-( ⁇ (2S,4EZ)-4-(chloromethylene)-l-[(4-chlorophenoxy)acetyl]pyrrolidinyl>- carbonyl -4-(3-4-dichlorophenyl pi ⁇ erazine
  • Example 59 (2S,4EZ)-4-benzylidene-l-[(4-chlorophenoxy acetyl]-N-(3,4-dimethoxy-benzyl)- 2-pyrrolidinecarboxamide
  • (2S,4EZ)-4-benzyli- dene-l-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid (4-chlorophenoxy)acetyl chlo-ride, and 3,4-dimethoxybenzylamine
  • MS( ⁇ SI+): m/z 521.6.
  • Example 63 (2S.4EZ)-N 2 -(1.3-benzodioxol-5-ylmethyl -4- ⁇ [(4-methoxybenzyl -oxy]imino>- N 1 -pentyl- 1.2-py ⁇ olidinedicarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- ⁇ [(4-methoxybenzyl)oxy]imino ⁇ -2- ⁇ y ⁇ olidinecarboxylic acid, 1-isocyanatopentane, and l,3-benzodioxol-5-ylmethylamine the title compound was obtained in 63% purity by LC/MS.
  • MS( ⁇ SI+): m/z 511.4.
  • Example 84 (2SAEZ)- 1 -(IT .1 '-bi ⁇ henvn-4-ylcarbonvn-N-r2-(diethylamino)ethyl]-4- (methoxyiminoV2-py ⁇ olidinecarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-py ⁇ olidinecarboxylic acid [1 ,1 '-biphenyl]-4-carbonyl chloride, andNl,Nl-diethyl-l,2-ethanediamine the title compound was obtained in 90% purity by LC/MS.
  • MS( ⁇ SI+): m/z 437.4.
  • Example 88 (2S.4EZ)-N-allyl-4- ⁇ r(3.4-dichlorobenzyl oxy1imino)-l-(diphenylacetyl)-2- pyrrolidinecarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- ⁇ [(3,4-dichlorobenzyl)oxy]imino ⁇ -2-py ⁇ olidinecarboxylic acid, diphenylacetyl chloride, and allylamine the title compound was obtained in 54% purity by LC/MS.
  • MS( ⁇ SI+): m/z 536.6.
  • Example 106 (2S.4EZ)-N 2 -cyclo ⁇ ropyl-4-
  • Example 110 (2S)- -(3.5-dichlorophenylVN2-(3.4-dimethoxybe ⁇ _zylV4-oxo-1.2- py ⁇ olidinedicarboxamide
  • Example 117 (2S,4EZ)-N-cyclopropyl-4- ⁇ [(3,4-dichlorobenzyl oxy]imino>-l-(diphenyl- acetyl -2-py ⁇ olidinecarboxamide
  • (2S,4EZ)-l-(tert-but- oxycafbonyl)-4- ⁇ [(3,4-dichlorobenzyl)oxy]imino ⁇ -2-py ⁇ olidinecarboxylic acid, diphenylacetyl chloride, and cyclopropylamme the title compound was obtained in 49% purity by LC/MS.
  • MS( ⁇ SI+): m z 536.6.
  • Example 135 (2S.4E , )-4-[(allylo ⁇ y)immo]-l-r4-(dimethylamino)butanoyll-N-(9-ethyl-9H- carbazol-3-yl)-2-py ⁇ olidmecarboxamide
  • Example 138 (2S.4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidine- carboxamide
  • (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(chloromethylene)-2-py ⁇ olidinecarboxylic acid, and 9-ethyl-9H-carbazol- 3-amine the title compoxmd was obtained in 73% purity by LC/MS.
  • MS( ⁇ SI+): m/z 354.4.
  • Example 147 (2S)-l-r(4-chlorophenoxy)acetyll-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2- pyrrolidinecarboxamide
  • Example 152 (2S,4EZ)-N-[2-(diethylamino)ethvn - 1 -(diphenylacetvD-4- (r(4-methoxyben- zyl)oxy]imino -2-pyrrolidinecarboxamide
  • (2S,4EZ)-l-(tert- butoxycarbonyl)-4- ⁇ [(4-methoxybenzyl)oxy]immo ⁇ -2-py ⁇ olidinecarboxylic acid, diphenylacetyl chloride, and N1,N1 -diethyl- 1,2-ethanediamine the title compoxmd was obtained in 56% purity by LC/MS.
  • MS( ⁇ SI+): m/z 557.4.
  • Example 156 (2S.4EZ -4-(cvanomethylene -N 1 -(3.5-dichlorophenvn-N 2 -(9-ethyl-9H-carba- zol-3-yl - 2-py ⁇ olidinedicarboxamide
  • Example 170 (2S-4EZ -4-r(benzylo ⁇ y imino]-N 2 -(9-ethyl-9H-carbazol-3-yl)-N 1 - ⁇ entyl-1.2- py ⁇ olidinedicarboxamide
  • Example 180 (2S.4EZ)-l-r(4-chloro ⁇ heno ⁇ y ⁇ acetyl1-4-(etho ⁇ yiminoVN-(9-ethyl-9H- carbazol-3-yl -2-py ⁇ olidmecarboxamide
  • Example 185 (2SAEZ)-l-( ⁇ ⁇ r-biphenyl]-4-ylcarbonyl -4-(ethoxyimino -N-(9-ethyl-9H- carbazol-3-yl)-2-py ⁇ olidinecarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-py ⁇ olidinecarboxylic acid, [1 ,1 '-biphenyl] -4-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70% purity by LC/MS.
  • MS( ⁇ SI+): m z 545.4.
  • Example 193 (2S.4EZ)-4-r(benzylo ⁇ y)imino]-l-r(2-oxo-6- ⁇ entyl-2H-pyran-3-yl carbonyll-N- (6-quinolinyl -2-py ⁇ olidinecarboxamide
  • (2S,4EZ)-4-[(benzyl- oxy)imino]-l -(tert-butoxycarbonyl)-2-py ⁇ olidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3- carbonyl chloride, and 6-quinolinamine the title compound was obtained in 48% purity by LC/MS.
  • MS( ⁇ SI+): m/z 553.4.
  • Example 215 (2S.4-5Z.-1 -ff 1.r-biphenyl1-4-ylcarbonvn-N-(9-ethyl-9H-carbazol-3-vn-4- (methoxyimino)-2-pyrrolidinecarboxamide
  • Example 222 (2S.4EZ)-N 1 -(3.5-dichlorophenyl)-N 2 -(9-ethyl-9H-carbazol-3-yl)-4-(methoxy- imino)- 1 ,2-py ⁇ olidinedicarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid 1 ,3-dichloro-5-isocyanato- benzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42% purity by LC MS.
  • MS( ⁇ SI+): m z 538.2.
  • Example 226 (2S.4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl -l-r(2-oxo-6-pentyl-2H- pyran-3-yl carbonyl -2-py ⁇ olidinecarboxamide
  • (2S,4EZ)-4-benzyli- dene-l-(tert-butoxycarbonyl)-2-py ⁇ olidinecarboxylic acid 2-oxo-6-pentyl-2H-pyran-3- carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine
  • MS( ⁇ SI+): m/z 588.4.
  • Example 230 (2S,4EZ)-4-[(allyloxy imino]-l -(2-ethoxy-l -naphthoyl)-N-(9-ethyl-9H-carba- zol-3 -yl -2- ⁇ y ⁇ olidinecarboxamide
  • (2S,4EZ)-4-[(allyl- oxy)-imino]-l-(tert-butoxycarbonyl)-2-py ⁇ olidinecarboxylic acid, 2-ethoxy-l-naphthoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 60% purity by LC/MS.
  • MS( ⁇ SI+): m/z 575.4.
  • Example 234 (2S,4EZ)-l-(n.r-biphenyl]-4-ylcarbonyl)-N-(tert-butyl)-4-(chloromethylene - 2-py ⁇ olidinecarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-py ⁇ olidinecarboxylic acid [1,1 '-biphenyl]-4-carbo-nyl chloride, and tert-butylamine the title compound was obtained in 80% purity by LC/MS.
  • MS( ⁇ SI+): m/z 397.6.
  • Example 235 tert-butyl 3-r(l4-methylene-l- (pentylamino carbonyl]-2-py ⁇ olidinyl car- bonvDamino]- 1 -azetidinecarboxylate
  • Example 238 (2S.4EZ)-l-acetyl-4- ⁇ r(3.4-dichlorobenzyl)o ⁇ y]iminol-N-(l-naphthyl-methylV 2-py ⁇ olidinecarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- ⁇ [(3,4-dichlorobenzyl)oxy]imino ⁇ -2-py ⁇ olidinecarboxylic acid, acetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 60% purity by LC/MS.
  • MS( ⁇ SI+): m/z 484.2.
  • Example 251 (2S.4EZ)-l-acetyl-4- ⁇ r(3.4-dichlorobenzyl)oxylimino)-N-(2-furylmethylV2- py ⁇ olidinecarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- ⁇ [(3,4-dichlorobenzyl)oxy]imino ⁇ -2-py ⁇ olidinecarboxylic acid, acetyl chloride, and 2-furylmethylamine the title compound was obtained in 199% purity by LC/MS.
  • MS( ⁇ SI+): m/z 424.6.
  • Example 252 (2S)-N 1 -(3.5-dichlorophenylV4-methylene-N 2 -(6-quinolinylV1.2-py ⁇ oli- dinedicarboxamide
  • Example 264 (2S,4EZ)-N-allyl-4-( (4-metho ⁇ ybenzv ⁇ oxy1iminol-l-( ⁇ henoxyacetylV2- pyrrolidinecarboxamide
  • (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- ⁇ [(4-methoxybenzyl)oxy]imino ⁇ -2-py ⁇ olidinecarboxylic acid, phenoxyacetyl chloride, and allylamine the title compoxmd was obtained in 72% purity by LC/MS.
  • MS( ⁇ SI+): m/z 438.2.
  • Example 268 (2S.4EZ)-4-r(allyloxy immo]-l-r4-(dimethylamino)butanoyl1-N-(l-na ⁇ hthyl- methyl)-2-py ⁇ olidmecarboxamide
  • (2S,4EZ)-4-[(allyl- oxy)imino]- 1 -(tert-butoxycarbonyl)-2-py ⁇ olidinecarboxylic acid, 4-(dimethylamino)buta-noyl chloride, and 1-naphthylmethylamine the title compoxmd was obtained in 85% purity by LC/MS.
  • MS( ⁇ SI+): m/z 437.2.
  • Example 273 tert-butyl 3-( ⁇ [(2S,4EZH-acetyl-4-benzylidenepwolidinyl] carbonyl) -amino)- 1 -azetidinecarboxylate

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Virology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Communicable Diseases (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention is related to pyrrolidine derivatives of formula (I). Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula (I) are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor. More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea. The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation, wherein X is selected from the group consisting of CR?6R7, NOR6, NNR6R7¿; A is selected from the group consisting of -(C=O)-, -(C=O)-O-, -C(=NH)-, -(C=O)-NH-, -(C=S)-NH, -SO¿2?2-, -SO2NH-, -CH2-,B is either a group -(C=O)-NR?8R9¿ or represents a heterocyclic residue having the formula (a) wherein Q is NR10, O or S; n is an integer selected of 0, 1 or 2; Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.

Description

PHARMACEUTICALLY ACTIVE PYRROLIDINE DERIVATIVES AS BAX INHIBITORS
Field of the invention
The present invention is related to pyrrolidine derivatives. Said compounds are preferably for use as pharmaceutically active compounds. Specifically, pyrrolidine derivatives of formula I are useful in the treatment and/or prevention of premature labor, premature birth and dysmenorrhea. In particular, the present invention is related to pyrrolidine derivatives displaying a substantial modulatory, notably an antagonist activity of the oxytocin receptor.
More preferably, said compounds are useful in the treatment and/or prevention of disease states mediated by oxytocin, including premature labor, premature birth and dysmenorrhea.
The present invention is furthermore related to novel pyrrolidine derivatives as well as to methods of their preparation.
Background of the invention
Oxytocin (OT) is a peptide hormone and causes the contraction of the uterus of mammals during labor. The corresponding Oxytocin receptor belongs to the family of G-protein-coupled receptors and is similar to Vιa and V2 vasopressin receptors. OT receptors increase dramatically during the course of pregnancy. The concentration of OT receptors has been shown to correlate with spontaneous uterine activity (M. Maggi et al. J. Clin.Endocrinol Metabol; 70; 1142, 1990). Premature labor, though, and premature birth is undesired as it represents a major cause of perinatal morbidity and mortality. Hence, the management of preterm labor represents a significant problem in the field of obstetrics.
In recent years, strong evidence has accumulated indicating that the hormone oxytocin plays a major role in iniating labor in mammals, notably in humans. Thereby, it is assumed that oxytocin exerts said effect in a direct as well as an indirect way, by contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may furthermore play a role in the cervical ripening process. This "up-regulation" of oxytocin receptors and increa-sed uterine sensitivity seems to be due to trophic effects of rising plasma levels of estrogen towards term. By down-regulating oxytocin, it is expected that both the direct (contractile) and indirect (increased prostaglandin synthesis) effects of oxytocin on the uterine could be blocked. An oxytocm modulator, e.g. blocker or antagonists would likely be more efficacious for treating prete m labor than current regimens. Moreover, as oxytocin at term has only an effect on the uterus, such an oxytocin modulator would have only few or no side efect.
A further condition being related to oxytocm is dysmenorrhea, which is characterised by cyclic pain associated with menses during ovulatory cycles. Said pain is believed to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the indirect and direct effects of oxytocin on the uterus, an oxytocin antagonost is belived more efficacious for treating dysmenorrhea than current regimens.
Some agents counteracting the action of Oxytocin (OT) are currently used in clinical stu-dies. Such tocolytic agents (i.e. uterine-relaxing agents) include beta-2-adrenergic agonists, magnesium sulfate and ethanol. The leading beta-2-adrenergic agonists is Ritodrine, which causes a number of cardiovascular and metabolic side effects, including tachycardia, increased renin secretion, hyperglycemia and reactive hypoglycemia in the infant. Further beta- 32-adrenergic agonists, including terbutaline and albuterol have side effcts similar to those of ritodrine. Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired. Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
The principal drawback to the use of peptide antagonists including also atosiban is the problem of low oral bioavailability resulting from intestinal degradation. Hence, they must be administered parenterally. The development of non-peptide ligands for pepetide hormone receptors are expected to overcome this problem. The first to report small molecule selective oxytocin antagonists was Merck. Apart from cyclic hexapeptides, Merck suggested indanylpiperidines and tolyl- piperazines as orally deliverable OT antagonists (Evans et al. JMed.Chem., 35, 3919 (1992). In WO 96/22775 and US-5,756,497 Merck reported benzoxazinylpiperidines or benzoxazinones as OT receptor antagonists.
It is a purpose ofthis invention to provide substances which more effectively down-regulate - up to antagonizing - the function of OT in disease states in animals, preferably mammals, especially in humans. It is another purpose ofthis invention to provide a method of antagonizing the functions of oxytocin in disease states of mammals. It is also an objective of the present invention to provide small molecule chemical compounds for the modulation, preferably the down-regulation or even antagonisation of the Oxytocin receptor. Moreover, it is an objective of the present invention to provide methods for preparing said small molecule chemical compounds. It is furthermore an objective of the present invention to provide a new category of pharmaceutical formulations for the treatment of preterm labor and dysmenorrhea, and/or diseases mediated by the Oxytocin receptor. It is finally an objective of the present invention to provide a method of treating or prevent disorders mediated by the Oxytocin receptor, like preterm labor and dysmenorrhea by antagonising the binding of Oxytocin to its receptor.
Description of the invention
The aforementioned objectives have been met according to the independent claims. Preferred embodiments are set out within the dependent claims which are incorporated herewith.
The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the mvention and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition. "Ci-Cβ -alkyl" refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.
"Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl). Preferred aryl include phenyl, naphthyl, phenantrenyl and the like.
"d-Cβ-alkyl aryl" refers to Cj-C6-alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
"Heteroaryl" refers to a monocyclic heteromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, l,3,4-oxadiazolyl,l,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3- dihydrojbenzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[l ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cirmnolinyl, napthyridinyl, pyrido[3,4- b]pyridyl, pyrido[3,2-b]ρyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8- tetrahydroquinolyl, 5,6,7,8-tetrehydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
"C Cβ-alkyl heteroaryl" refers to Ci-Cβ-alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(lH-indol-3-yl)ethyl and the like.
"Alkenyl" refers to alkenyl groups preferably having from 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation. Preferable alkenyl groups include ethenyl (- CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2) and the like. "Alkynyl" refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.
"Acyl" refers to the group -C(O)R where R includes "Q-Ce-alkyl", "aryl", "heteroaryl", "Q- Ce-alkyl aryl" or "Ci-Oalkyl heteroaryl".
"Acyloxy" refers to the group -OC(O)R where R includes "C C6-alkyl", "aryl", "heteroaryl", " -Ce-alkyl aryl" or "Q-Cβ-alkyl heteroaryl".
"Alkoxy" refers to the group -O-R where R includes "CrC6-alkyl" or "aryl" or "heteroaryl" or "Ci- -alkyl aryl" or " -Co-alkyl heteroaryl". Preferred alkoxy groups include by way of example, methoxy, ethoxy, phenoxy and the like.
"Alkoxycarbonyl" refers to the group -C(O)OR where R includes "CrCό-alkyl" or "aryl" or "heteroaryl" or "d-C6-alkyl aryl" or "Q-Ce-alkyl heteroaryl".
"Aminocarbonyl" refers to the group -C(O)NRR' where each R, R' includes independently hydrogen or Q-C.-alkyl or aryl or heteroaryl or "CrC6-alkyl aryl" or "Q-Ce-alkyl hetero- aryl".
"Acylamino" refers to the group -NR(CO)R' where each R, R' is independently hydrogen or "Ci-Cβ-alkyP or "aryl" or "heteroaryl" or "d-C.-alkyl aryl" or "Q-C6-alkyl heteroaryl".
"Halogen" refers to fluoro, chloro, bromo and iodo atoms.
"Sulfonyl" refers to group "-SO2-R" wherein R is selected from H, "aryl", "heteroaryl", "C Cβ-alkyl", "d-Ce-alkyl" substituted with halogens e.g. an -SO2-CF3 group, " -Cβ-alkyl aryl" or "Q-C6-alkyl heteroaryl".
"Sulfoxy" refers to a group "-S(O)-R" wherein R is selected from H, "d-Ce-alkyl", "Q-C6- alkyl" substituted with halogens e.g. an -SO-CF3 group, "aryl", "heteroaryl" , "Q-Ce-alkyl aiyl" or "C C6-alkyl heteroaryl". "Thioalkoxy" refers to groups -S-R where R includes "d-Cδ-alkyl" or "aryl" or "heteroaryl" or "CrCδ-alkyl aryl" or "CrC.-alkyl heteroaryl". Preferred thioalkoxy groups include thiomethoxy, thioethoxy, and the like.
"Substituted or unsubstituted" : Unless otherwise constrained by the definition of the indi- vidual substituent, the above set out groups, like "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl" etc. groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of "Cι-C6-alkyl", "Cι-C6-alkyl aryl", "Q-C.-alkyl heteroaryl", "C2- Cδ-alkenyl", "C2-C6-alkynyl", primary, secondary or tertiary amino groups or quarternary ammonium moieties, "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "aryl", "heteroaryl", carboxyl, cyano, halogen, hydroxy, mercapto, nitro, sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like. Alternatively said substitution could also comprise situations where neighboring substituents have undergone ring closure, notably when viccinal functional substituents are involved, thus forming e.g. lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
"Pharmaceutically acceptable salts or complexes" refers to salts or complexes of the below- identified compounds of formula I that retain the desired biological activity. Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disul-fonic acid, and polygalacturonic acid. Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quarternary ammonium salt of the formula -NR,R',R" + Z", wherein R, R', R" is independently hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate). "Pharmaceutically active derivative" refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
"Enantiomeric excess" (ee) refers to the products that are obtained by an asymmetric synthesis, i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded. In the absence of an asymmetric synthesis, racemic products are usually obtained that do however also have the inventive set out activity as OT-R antagonists.
Quite surprisingly, it was now found that pyrrolidine derivatives according to formula I are suitable pharmaceutically active agents, by effectively modulating, in particular by effectively inhibiting the OT-R function and more specifically by antagonising the oxytocin receptor.
When the oxytocin receptor is bound by the compounds according to formula I, oxytocin is antagonised by being blocked from its receptor and is therefore unable to exert its biologic or pharmacological effects. The compounds of the present invention are therefore in particular useful in the treatment and/or prevention of oxytocm-related disorders of mammals and in particular of humans. These disorders mediated by the oxytocin receptor, are primarily preterm labor and dysmenorrhea.
The compounds according to the present invention are those of formula I.
Said formula also comprises its geometrical isomers, its optically active forms as enantio- mers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts of the compound I, are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and para- toluenesulfonate salts.
h said formula I, X is selected from the group consisting of CR6R7, NOR6, NNR6R7.
A is selected from the group consisting of -(C=O)-, -(C=O)-O-, -C(=NH)-,-(C=O)-NH-, - (C=S)-NH, -SO2-, -SO2NH-, -CH2-.
B is either an amido group of the formula -(C=O)-NR8R9 or B represents a heterocyclic residue having the formula B1
wherein Q is NR10, O or S; n is an integer selected of 0, 1 or 2, preferably 0. m is an integer selected of 0, 1, 2 or 3, preferably 0 or 1.
Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring.
R1 is selected from the group comprising or consisting of unsubstituted or substituted CrC6- alkyl, unsubstituted or substituted C -C6-alkenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, acyl, unsubstituted or substituted Cj-Cβ-alkyl aryl, unsubstituted or substituted d-Cό-alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl group. R2, R3, R4 and R5 are independently selected from each other from the group consisting of hydrogen, halogen, Ci-Cg-alkyl, Q-C6-alkoxy, preferably they are all hydrogen.
R6 and R7 are independently selected from the group comprising or consisting of hydrogen, unsubstituted or substituted C C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsub- stituted or substituted C2-C6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted saturated or xmsaturated 3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted Q-Cό-alkyl aryl, unsubstituted or substituted CrCβ-alkyl heteroaryl.
R8, R9 and R10 are independently selected from the group comprising or consisting of hydrogen, unsubstituted or substituted C]-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl.
Alternatively, each pair R6, R7 and/or R8, R9 could form together with the N atom to which they are attached a 3-8 membered substituted or unsubstituted, saturated or unsaturated heterocyclic ring which may contain 1-2 further heteroatoms selected from N, S and O and which is optionally fused with an aryl, heteroaryl or 3-8 membered saturated or unsaturated cycloalkyl ring.
R11 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted Cι-C6-alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary or tertiary amino groups or quarternary ammonium moieties, unsub-stituted or substituted saturated or unsaturated 3-8-membered cycloalkyl. Preferred pyrrolidine derivatives are those compounds according to formula I wherein B is a group -(C=O)-NHR9, in which R9 is selected from the group consisting of unsubstituted or substituted Q-C6 alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted saturated or xmsaturated 3-6-membered cycloalkyl which optionally contains a N atom, unsubstituted or substituted aryl, unsubstituted or sub-stituted heteroaryl, unsubstituted or substituted C1-C2-alkyl aryl, unsubstituted or substi-tuted C1-C-2- alkyl heteroaryl.
Preferred heteroaryls are pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzo-thienyl, 2,1,3- benzothiadiazolyl, 2,1,3-benzoxadiazolyl, benzodioxolyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[l,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8- tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, acridinyl or benzoquinolyl and whereby said heteroaryl could be fused with a 3-8-membered cycloalkyl containing optionally 1-3 heteroatoms selected from N, O, S.
According to a further preferred embodiment the pyrrolidine derivatives according to the present invention carry a residue B1 which is a fused heterocycle of the formula
Particularly preferred pyrrolidine derivatives are those compounds according to formula I wherein X is NOR6, and R6 is selected from the group consisting of H, unsubstituted or substituted Ci-Cβ alkyl, xmsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted acyl, unsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3- 8-membered cycloalkyl, xmsubstituted or substituted d-C6-alkyl aryl, unsubstituted or substituted d-Cό-alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl groups. Particularly preferred R6 is H, CH3, xmsubstituted or substituted CH2-phenyl or allyl.
Under no circumstances B could be a group COOR or a group -(C=O)NR(OR), whereby R is H, alkyl or acyl. Such compounds, notably having a group B = hydroxamic acid are des-cribed in WO 99/52868 as being potent inhibitors of metalloproteases.
Further particularly preferred pyrrolidine derivatives are those compounds according to formula I wherem X is CHR6, and R6 is selected from the group consisting of halogen, cyano, unsubstituted or substituted C3-C6 alkyl, xmsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted d-C6-alkyl aryl, xmsubstituted or substituted d-Cδ-alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl groups. Particularly preferred R6 is halogen, cyano, d-C6 alkyl or an unsubstituted or substituted phenyl group.
According to a further preferred embodiment the pyrrolidine derivatives have a substituent A being -(C=O)-, or -(C=O)-NH-, or -SO2-, most preferred is -(C=O)-.
More preferred groups R1 are substituted or unsubstituted d-Cβ-alkyl, Q-Ce-alkenyl, xmsubstituted or substituted C -C6-alkynyl, aryl, heteroaryl, saturated or xmsaturated 3-8- membered cycloalkyl and still more preferred R1 are CrCβ-alkyl or aryl. A particularly preferred substituent R1 is biphenyl.
Accordmg to a most preferred embodiment, the pyrrolidine derivatives according to formula I are those wherein X is =NOR6 or =CHC1, R6 is a d-C6-alkyl, e.g. a methyl group, or aryl or d-C6-alkyl aryl group, A is -(C=O)- and R1 is a d-C6-alkyl or aryl or Cι-C6-alkyl aryl group. Even more preferred are those pyrrolidine derivatives, wherem X is =NOR6, or =CHC1, R6 is methyl, B is an amido group of the formula -(C=O)NHR9, wherein R9 is an unsubstituted or substituted d-Cβ-alkyl aryl group, e.g. a substituted phenylethyl group, A is -(C=O)- and R1 is a substituted or unsubstituted biphenyl or an acetylmethyl group.
The compounds of formula I may contain one or more asymmetric centers and may therefore exist as enantiomers or diasteroisomers. It is to be understood that the invention inclu-des both mixtures and separate individual isomers or enantiomers of the compounds of formula I. In a particularly preferred embodiment the pyrrolidine derivatives according to formula I are obtained in an enantiomeric excess of at least 52 % ee, preferably of at least 92-98% ee. Also E/Z isomers with regard to pyrrolidine derivatives having residues X being =CR R whereby both R6R7 are different from each other, and/or with regard to pyrrolidine derivatives having residues X being =NOR6 or =NNR6R7 are comprised by the present invention.
Specific examples of compounds of formula I include the following:
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrro- lidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biρhenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2- phenethyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyemyl)-4-(methoxyimino)-2-pyrro- lidinecarboxamide
(2S,4EZ)-l-([l,r-biρhenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-ρhenethyl]-4-(methoxy- imino)-2-pyrrolidinecarboxamide
(3EZ,5S)-5-(lH-benzimidazol-2-yl)-l-([l,l'-biphenyl]-4-ylcarbonyl)-3-ρyrrolidinone O- methyloxime
(2S,4EZ)-N-(2,l,3-benzothiadiazol-4-yl)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxy-imino)- 2-pyrrolidinecarboxamide (2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimmo)-N-(6-quinolmyl)-2-pyrrolidine- carboxamide
(2S,4EZ)-l-acetoacetyl-N-benzyl-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,r-biρhenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-fiιrylmethyl)-2- pyrrolidinecarboxamide
(2S,4EZ)-l-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2- hydroxy-2-phenethyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-allyl- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbox- amide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2-ρyrroli- dinecarboxamide
(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-l-[(2-oxo-6-ρentyl-2H-ρyran-3-yl)carbonyl]- 2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,r-biρhenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxyimino)-2-pyrroli- dinecarboxamide
(2S,4EZ)- 1 -acetyl-N-cyclopropyl-4- {[(3,4-dichlorobenzyl)oxy]imino} -2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)-l-[(2-oxo-6-pentyl-2H-pyran-3-yl)car-bonyl]- 2-pyrrolidinecarboxamide
(2S,4EZ)-N-benzyl- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-4-(methoxyimino)-N-methyl-2-pyrroli- dinecarboxamide
(2S,4EZ)-l-(diρhenylacetyl)-4-(ethoxyimino)-N-(2-tMenylmethyl)-2-pyrrolidinecarbox-amide (2S,4EZ)-N-(2, 1 ,3-benzothiadiazol-4-yl)-4-(cyanomethylene)- 1 -(diphenylacetyl)-2-pyrroli- dinecarboxamide
(3EZ,5S)-5-(lH-benzimidazol-2-yl)-l-(diphenylacetyl)-3-pyrrolidinone O-methyloxime
(2S)-2-[ 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyrrolidinyl]-lH-benzimidazole
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-methoxyethyl)-2- pyrrolidinecarboxamide
(3EZ,5S)-5-(lH-benzimidazol-2-yl)- 1 -(diphenylacetyl)-3-pyrrolidinone O-allyloxime
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-l-(diρhenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-thienylmethyl)-2- pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-l-acetoacetyl-4-(methoxyimino)-N-(l-naphthylmethyl)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-l-(diphenylacetyl)-2-pyrrolidinecar- box-amide
(2S,4EZ)-4- { [(3,4-dichlorobenzyl)oxy]imino} -N1 -pentyl-N2-(6-quinolinyl)- 1 ,2-pyrrolidine- dicarboxamide
(2S,4EZ)-4-(chloromethylene)-l-(diphenylacetyl)-N-[(2i?S)-2-hydroxy-2-ρhenethyl]-2-pyrroli- dinecarboxamide
(2S)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-methylene-2- pyrrolidine-carboxamide (2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)- N-(6-quinolinyl)-2-pyrroli- dinecarboxamide
(2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-l-(diphenylacetyl)-2-pyrrolidinecarbox- amide
(2S,4EZ)-l-acetoacetyl-4-(methoxyimino)-N-(2-thienylmethyl)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2ΛS)-2-hydroxy-2-ρhenethyl]-2- pyrro-lidinecarboxamide
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N1-(3,5-dichlorophenyl)-N2-(6-quinolinyl)-l,2- pyrrolidinedicarboxamide
(2S,4EZ)-4-(methoxyimino)-N-(l-naphmylmemyl)-l-(phenoxyacetyl)-2-pyrrolidinecarbox- amide
(2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-l-[(2-oxo-6-ρentyl-2H-pyran-3- yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)- 1 -(diphenylacetyl)-4-(methoxyimino)-N-(2 -thienylmethyl)-2-pyrrolidinecarbox- amide
(2S,4EZ)-N-benzyl-l-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4- {[(3 ,4-dichlorobenzyl)oxy]imino} -N-[2- (diethylammo)ethyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-l-[4-(dimethylamino)butanoyl]-N-(6-quino- linyl)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-(5-ethyl-l,3,4-thiadiazol-2-yl)-4-(methoxy- imino)-2-pyrrolidinecarboxamide (2S,4EZ)-N-benzyl- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidine- carboxamide
(2S,4EZ)-N-benzyl-l-(diphenylacetyl)-4-(ethoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N2-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N1-(3-methoxyphenyl)-l,2- pyrrolidinedicarboxamide
(2S,4EZ)-l-(diρhenylacetyl)-N-[(2RS)-2-hydroxy-2-ρhenethyl]-4-{[(4-methoxybenzyl)- oxy]imino} -2-pyrrolidinecarboxamide
(2S)-N-(2-furylmethyl)-4-methylene-l-[(2-oxo-6-ρentyl-2H-pyran-3-yl)carbonyl]-2- pyrrolidine-carboxamide
(2S,4E2)-N-(2,l,3-benzot_ήadiazol-4-yl)-l-(diphenylacetyl)-4-(methoxyimino)-2-pyrrolidine- carboxamide
(2S,4EZ)-N-benzyl-l-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidine- carboxamide
(2S,4EZ)-l-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-qumolinyl)-2-pyrrolidinecar- boxamide
(2S,4EZ)-l-acetoacetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2- pyrrolidinecarboxamide
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N2-[(2RS)-2-hydroxy-2-phenethyl]-N1-pentyl- 1 ,2-pyrrolidinedicarboxamide
(2S,4EZ)-4-[(benzyloxy)imino]-N-(l-naphmylmethyl)-l-(phenoxyacetyl)-2-pyrrolidinecar- boxamide
(2S)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-4-methylene-N-(6-quinolinyl)-2-pyrrolidinecarbox- amide (2S,4EZ)-N-cycloproρyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-l-(diphenylacetyl)-2-pyrroli- dinecarboxamide
(2S,4EZ)- 1 -(4-cyanobenzoyl)-4- {[(3 ,4-dichlorobenzyl)oxy]imino} -N-(6-quinolinyl)-2- pyrrolidinecarboxamide
(2S,4EZ)-N-cycloρropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-l-(methoxyacetyl)-2-pyrroli- dinecarboxamide
(2S,4EZ)-N-(l,3-benzodioxol-5-ylmethyl)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-(methoxy- imino)-2-pyrrolidinecarboxamide
(3EZ,5S)-5-[(4-acetyl-l-piperazmyl)carbonyl]-l-acryloyl-3-pyrrolidmone O-(3,4-dichloro- benzyl)oxime
(2S)- 1 -([ 1 , 1 -biphenyl] -4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrrolidinecarbox- amide
(2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-l-[(2-oxo-6-pentyl-2H-pyran-3- yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2R5)-2-hydroxy-2-phenylethyl]-4-(memoxyimino)-l-[(2'-methyl[l,l'-biphenyl]- 4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-3-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-(4-benzoylbenzoyl)-N-[(2RS)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-(3-ρhenoxybenzoyl)-2- pyrrolidinecarboxamide (2S,4EZ)-N-[(2RS)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)-l-(2-phenoxybenzoyl)-2- pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]- 4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biρhenyl]- 4-yl)carbonyl]-2-ρyrrolidinecarboxamide
(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]-4-yl)carbonyl]- 2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-N-methyl- 1 -[(2'-methyl[l , 1 *-biρhenyl]-4- yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l*-biphenyl]-4-ylsulfonyl)-N-[(lS,2S,3R,4i?)-3- (hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-(trarø-4-hydroxycyclohexyl)-4-(methoxyimmo)- 2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(lR,2R)-2-(hydroxymethyl)cyclohexyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxyproρyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-pyrrolidmecarboxamide
(2S,4EZ)-1-([1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxyproρyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide (2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-[(l-hydroxycyclohexyl)methyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(l-hydroxycyclohexyl)methyl]-4-(methoxyimmo)-l-[4-(3-pyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(l-hydroxycyclohexyl)methyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2- hydroxyethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[4-(4-ρyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimmo)-l-[4-(3-pyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)-l-[4-(2-ρyridmyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4-(methoxyimmo)- 2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l*-biρhenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxyproρyl]-4-(methoxyimino)- 2-pyrrolidinecarboxamide (2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4- methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-pyrrolidmecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-(4-methoxyphenoxy)- propyl]-4-(methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-1 -([ 1 , 1 '-biρhenyl]-4-ylcarbonyl)-N-[(2i?S)-2-hydroxyproρyl]-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(2i?S)-2-hydroxy-2-(2-naphthyl)ethyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2R5)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitroρhenyl)ethyl]-4-(methoxyimino)-l-[4-(4- pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-l-[4-(2- pyridinyl)benzoyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide (2S,4EZ)-N-{(2ΛS)-3-[4-(acetylamino)phenoxy]-2-hydroxyρropyl}-l-([l,r-biρhenyl]-4- ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-l-[4- (4-pyridinyl)benzoyl]-2 -pyrrolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-l-[4- (3 -pyridinyl)benzoyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)ρhenoxy]-2-hydroxypropyl}-l-([l,l'-biρhenyl]-4- ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[4-(4-pyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4E^-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[4-(3-ρyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl] -4-(methoxyimino)- 1 -[4-(2-pyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-1 -([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-(3-hydroxyproρyl)-4-(memoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-l-([l,r-biρhenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2- pyrrolidmecarboxamide (3EZ,5S)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-l -piperidinyl)carbonyl]-3- pyrrolidinone O-methyloxime
(3EZ,5S)-5-[(4-hydroxy-4-phenyl-l-piperidmyl)carbonyl]-l-[4-(4-pyridinyl)benzoyl]-3- pyrrolidinone O-methyloxime
(3EZ,5S)-5-[(4-hydroxy-4-ρhenyl-l-piperidinyl)carbonyl]-l-[4-(3-pyridinyl)benzoyl]-3- pyrrolidinone O-methyloxime
(3EZ,5S)- 1 -([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-ρhenyl-l -piperidinyl)carbonyl] -3- pyrrolidinone O-methyloxime
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(lS,2S)-2-hydroxycyclohexyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylsulfonyl)-N-[(lS,2S)-2-hydroxycyclohexyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-N-benzyl- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4E2)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-l-[4-(3-pyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(3EZ,5S)-l-([l,r-biphenyl]-4-ylcarbonyl)-5-{[(3i?S)-3-hydroxypiperidinyl]carbonyl}-3- pyrrolidinone O-methyloxime
(3EZ,5_S)-5-{[(3R )-3-hydroxypiperidinyl]carbonyl}-l-[4-(4-pyridinyl)benzoyl]-3- pyrrolidinone O-methyloxime
(3EZ,5S)-5-{[(3RS)-3-hydroxypiperidinyl]carbonyl}-l-[4-(3-ρyridmyl)benzoyl]-3- pyrrolidinone O-methyloxime (3EZ,5S)-1 -([1 ,l'-biphenyl]-4-ylsulfonyl)-5- {[(3RS)-3-hydroxypiperidinyl]carbonyl} -3- pyrrolidinone O-methyloxime
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2- phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-l-[4-(4- pyridmyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-phenylethyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2- phenylethyl] -4-(methoxyimmo)-2-pyrrolidmecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)- 1 -([1,1 '-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4E^-N-(2-anilinoethyl)-4-(methoxyimino)-l-[4-(4-pyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimmo)-l-[4-(3-ρyridinyl)benzoyl]-2- pyrroli dinecarboxamide
(2S,4EZ)-N-(2-amlinoethyl)-4-(methoxyimino)-l-[4-(2-ρyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-l-([l,l'-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide
(3EZ,5S)-l-([l,l'-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-l-piρeridinyl)carbonyl]-3- pyrrolidinone O-methyloxime (3EZ,5S)- 1 -([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy- 1 -piperidinyl)carbonyl]-3- pyrrolidinone O-methyloxime
(2S,4EZ)-N-[(lS,2R,3S,4Λ)-3-(aminocarbonyl)bicyclo[2.2. l]hept-5-en-2-yl]-l -([1 , 1 '- biphenyl]-4-ylsulfonyl)-4-(methoxyimmo)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(3-amino-3-oxopropyl)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-N-[(lS,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-l-([l,r- biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-py_τolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-1 -([1 , 1 '-biρhenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxyimmo)-2- pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(lR,2R)-2-(hydroxymethyl)cyclohexyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1-([1 ,l'-biphenyl]-4-ylsulfonyl)-N-[(lΛ,2S,3R,4S)-3-(hydroxymethyl)bicyclo. [2.2.1 ]hept-2-yl]-4-(methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(li?,2S)-2-(hydroxymethyl)cyclohexyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4E and 4Z)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)- 1 -[(2'-methyl[ 1 , 1 '- biphenyl]-4-yl)carbonyl]-2-ρyrrolidmecarboxamide
(2S,4E and 4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (2S,4E and 4Z)-N-[(2i-)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l ,1'- biphenyl] -4-yl)carbonyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-[(lR,2S)-2-(hydroxymethyl)cyclohexyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-[2-hydroxy-l-(hydroxymethyl)ethyl]-4- (methoxyimmo)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(lS,2Λ,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-l-([l,l'- biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4E2)-N-[(lS,2S,3i?,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-l-([l,r- biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2RS)-3-({[(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)ρyrrolidinyl]- carbonyl} amino)-2-hydroxypropanoic acid
(2S,4EZ)-N-[(li?,2S)-2-(aminocarbonyl)cyclohexyl]-l-([l,r-biphenyl]-4-ylcarbonyl)-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(lRS)-2-hydroxy-l-methylethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-(4- nitrophenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
4-({[(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}- amino)butanoic acid (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-l-[(2*-methoxy[l,r-biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyrrolidmecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-l-[(2'-methoxy[l,l'-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(li?S)-2-hydroxy-l-methylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biphenyl]- 4-yl)carbonyl]-2-pvrrolidinecarboxamide
(2S,4EZ)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4- (methoxyimino)-l -[(2'-methyl[ 1 , 1 '-biphenyl] -4-yl)carbonyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-(4-nitroρhenyl)ethyl]-4- (methoxyimino)-l-[(2'-methoxy[l,r-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(3EZ,5S)-5-[(4-hydroxy-l-piperidinyl)carbonyl]-l-[(2'-methyl[l,l'-biρhenyl]-4-yl)carbonyl]- 3 -pyrrolidinone O-methyloxime
(2S,4EZ)-N-[(lS,2S,3R,4i2)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-4- (methoxyimiho)- 1 -[(2'-methyl[ 1 , 1 '-biphenyl] -4-yl)carbonyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-l-[(2'-methoxy[l,r-biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biphenyl]-4- yl)carbonyl]-2-pyrroli dinecarboxamide
(2S,4EZ)-N-[(2RS)-2,3-dihydroxyproρyl]-4-(methoxyimino)-l -[(2'-methyl[ 1 , 1 '-biphenyl]-4- yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimino)- 1 -[(2'-methyl[ 1 , 1 '-biphenyl]-4- yl)carbonyl]-2-pyrrolidinecarboxamide (2S,4EZ)-N-(2-amino-2-oxoethyl)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-l -[(2'-methyl[ 1 , 1 '-biphenyl] -4- yl)carbonyl]-2-pyrrolidmecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(lS,2R,3S,4i?)-3-(hydroxymethyl)- bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(li?,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1 ]hept-2-yl]- 1 -[(2'-methoxy[l , 1 "- biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(trα«_s-4-hydroxycyclohexyl)-l-[(2'-methoxy[l, -biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(l^,2R)-2-(hydroxymethyl)cyclohexyl]-l-[(2'-methoxy[l,r-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-ρyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2'- methyl[l, -biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2'- methoxy[l,r-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-l-[(2'-methyl[l,l'- biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxy-3-methoxyρhenyl)ethyl]-l-[(2'-methoxy[l,r- biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-l-[(2'-methoxy[l,r-biphenyl]- 4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2R,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biρhenyl]- 4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2'-cyano[l,l'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)- 1 -[(3 ',4'-dichloro[l , 1 '-biphenyl]-4-yl)carbonyl]-N-[(2i?S)-2-hydroxy-2- phenylethyl]-4-(methoxyimino)-2-ρyrrolidinecarboxamide
(2S,4EZ)-l-[(2',6'-dimethyl[l,r-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2- ρhenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-phenylethyl]- 4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2'- methyl[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2'- cyano [1,1 '-biphenyl] -4-yl)carbonyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(3',4'- dichloro[ 1 , 1 '-biρhenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimmo)-l-[(2',6'- dime thyl[ 1 , 1 '-biphenyl] -4-yl)carbonyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2',3- dimethyl[ 1 , 1 '-biphenyl] -4-yl)carbonyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(3',4'-dichloro[l,l'-biphenyl]-4-yl)carbonyl]-N-[(2i?S)-2-hydroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',6'-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',6'-dimethyl[l,r-biphenyl]-4-yl)carbonyl]-N-[(2i_S)-2-hydroxy-3-(4- methoxyphenoxy)propyl]-4-(methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4- methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-l-[(2',6'-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)- 1 -[(2',3-dimethyl[l , 1 '-biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(3-ammo-3-oxoρropyl)-l-[(2',6'-dimethyl[l,l'-biρhenyl]-4-yl)carbonyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-N-(3-amino-3-oxoρropyl)- 1 -[(2',3-dimethyl[l , 1 '-biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide (2S,4EZ)- 1 -[(2',6'-dimethyl[l , 1 '-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy- 1 - (hydroxymethyl)ethyl]-4-(methoxyimmo)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',3-dimethyl[l,r-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy-l-(hydroxy- methyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2'-cyano[l,l'-biphenyl]-4-yl)carbonyl]-N-[(lR,2R)-2-(hydroxymethyl)- cyclohexyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(3EZ,5S)-5-(3,4-dihydro-2(lH)-isoquinolinylcarbonyl)-l-[(2',3-dimethyl[l,l'-biphenyl]-4- yl)carbonyl] -3 -pyrrolidinone O-methyloxime
(2S,4EZ)-N-[(lR)-2-hydroxy-l-phenylethyl]-4-(methoxyimmo)-l-[(2'-methyl[l,l'-biρhenyl]- 4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',6'-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',3-dimethyl[l,l'-biρhenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',6'-dimemyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[(lR,2S)-2-hydroxy-l,2- diphenylethyl]-4-(methoxyimmo)-2-pyrrolidinecarboxamide
(2RS)-2-[( {(2S,4EZ)-4-(methoxyimino)-l -[(2'-methyl[ 1 , 1 '-biphenyl] -4-yl)carbonyl]- pyrrolidinyl}carbonyl)amino]-3-phenylpropanoic acid (2S,4EZ)-N-[(li?,2S)-2-(aminocarbonyl)cyclohexyl]-l-[(2',6'-dimethyl[l,r-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(lR,2S)-2-(aminocarbonyl)cyclohexyl]-l-[(2*,3-dimethyl[l,l'-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
4'-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-l-piperazinyl]carbonyl}-4-(methoxyimino)- pyrrolidinyl] carbonyl} [1,1 '-biphenyl] -2-carbonitrile
(3EZ,5S)-l-[(3*,4'-dichloro[l,l*-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-l- piperazinyl]carbonyl} -3 -pyrrolidinone O-methyloxime
(3EZ,5S)-l-[(2',6'-dimethyl[l,r-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-l- piperazinyl]carbonyl}-3-pyrrolidinone O-methyloxime
(3EZ,5S)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-l- piperazinyl]carbonyl} -3 -pyrrolidinone O-methyloxime
(3EZ,5S)-l-[(2'-methyl[l,l'-biρhenyl]-4-yl)carbonyl]-5-({4-[4-(trifluoromethyl)phenyl]-l- piperazinyl} carbonyl)-3-pyrrolidinone O-methyloxime
(3EZ,5S)-l-[(2'-methyl[l,l'-biphenyl]-4-yl)carbonyl]-5-({4-[3-(trifluoromethyl)phenyl]-l- piperazinyl} carbonyl)-3-pyrrolidinone O-methyloxime
(2S,4EZ)-4-(methoxyimino)-l-[(2'-methyl[l,r-biρhenyl]-4-yl)carbonyl]-2-ρyrrolidine- carboxamide
(2S,4EZ)-4-(methoxyimino)-N-methyl-l-[(2'-methyl[l,l'-biρhenyl]-4-yl)carbonyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-4-(methoxyimmo)-N V-dimethyl-l -[(2'-methyl[ 1 , 1 *-biρhenyl]-4-yl)carbonyl]-2- pyrrolidinecarboxamide (2S,4EZ)-N-[(3R)-3-hydroxy-3-phenylρropyl]-4-(methoxyimino)-l-[(2'-methyl[l,r-biρhenyl]- 4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biρhenyl]- 4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-1 -([ 1 ,l'-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-ρhenylpropyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-{[2*-(trifluoro-methyl)[l,l'- biphenyl] -4-yl] carbonyl} -2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l - {[2'-chloro[l , 1 '-biphenyl] -4- yl]carbonyl} -2-pyrrolidinecarboxamide
(2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]-4- yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[2-(hydroxymethyl)ρhenyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biρhenyl]-4- yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimmo)-l -[(2-methyl[l , l'-biρhenyl]-4- yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4E and 4Z)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]-4-yl)carbonyl]-N-(2-ρhenylethyl)-2- pyrrolidinecarboxamide Thereby, the most preferred compounds are those which are selected from the group consisting of:
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2- phenethyl] -2-pyrrolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrro- lidinecarboxamide
(2S,4EZ)-l-([l,l*-biphenyl]-4-ylcarbonyl)-N-[(2i-S)-2-hydroxy-2-phenethyl]-4- (methoxyimino)-2 -pyrrolidinecarboxamide
(3EZ, 5S)-5-( lH-benzimidazol-2-yl)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-3 -pyrrolidinone O- methyloxime
(2S,4EZ)-N-(2, 1 ,3-benzothiadiazol-4-yl)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)- 2-pyrrolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-4-(methoxyimino)-N-(6-qumolinyl)-2-pyrrolidme- carboxamide
(2S,4Z)-Ν-[(2_S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2"-methyl[l,r-biρhenyl]-4- yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biphenyl]-4- yl)carbonyl]-2-pyrrolidinecarboxamide
A further aspect of the present invention is related to the use of the pyrrolidine derivatives according to formula I for the preparation of pharmaceutical compositions for the treatment and/or prevention of premature labor, premature birth, for stopping labor prior to cesarean delivery and dysmenorrhea. Preferably, the compounds according to formula I are suitable for the modulation of the OT function, thus specifically allowing the treatment and/or pre-vention of disorders which are mediated by the oxytocin receptor. Said treatment involves the modulation - notably the down regulation or the antagonisation - of the oxytocin recep-tor.
More specifically, the compounds of the present mvention are useful for the treatment of preterm labor, premature birth, dysmenorrhea and for stopping labor prior to cesarean delivery.
Still a further aspect of the present invention is related to the actually novel pyrrolidine compounds of formula I. Some very few compounds have actually been disclosed prior to the filing of the present application, without any medical use though. Said known corn-pounds of formula I are those, wherein
X is (=CH2), A is -(C=O)-O-, R1 is a t-butyl group and B is -(C=O)-NMe2 (Tetrahedron 53(2), 539, 1997); -(C=O)-NHMe (WO 95/47718); -(C=O)-NH-CH(Me)-(C=O)-NH-CH(Me)- COOH (WO 95/47718); or -(C=O)-NH-CH(COOCH2-Ph)-CH2-COOPh (Tetrahedron 48(31), 6529, 1992).
X is (=CHR6) with R6 being cyclohexylmethyl, A is -(C=O)-O-, R1 is a t-butyl group and is - (C=O)-NH-t-butyl (Biorg. Chem.Lett. 3(8), 1485, 1993).
X is C1-C20 alkylidene, A is -(C=O)-O-, R1 is a t-butyl and B is
wherein R is Cι-C12 alkyl and Hal is Cl, Br, J. Said compoxmds are disclosed in DE-1, 932,823 as intermediates.
X is C1-C20 alkylidene, A-R1 is a protective group and B is
with R being H or d-C12 alkyl (GB- 1,118,306)
Hence, the novel compounds are those of the formula I, wherein the above mentioned known compounds are excluded.
Still a further object of the present invention is a process for preparing the pyrrolidine derivatives accordmg to formula I.
The pyrrolidine derivatives exemplified in this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the parti-cular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimisation procedures.
Generally, the pyrrolidine derivatives according to the general formula I could be obtained by several processes, using both solution-phase and solid-phase chemistry protocols. Depending on the nature of A, B, and X, certain processes will, in some instances, be preferred over others, and it is assumed that the choice of the most suitable process will be known to the practitioner skilled in the art.
According to one process, pyrrolidine derivatives according to the general formula I, whereby the substituent B is C(O)-NR8R9, with R8 and R9 being defined as above, are prepared from the corresponding suitably N-protected 4-substituted pyrrolidine derivatives II, whereby the substituent X is as above defined, by solution-phase chemistry protocols such as described in the Examples and shown in Scheme 1, below. The suitably N-protec-ted 4-substituted pyrrolidine derivatives II are first reacted with primary or secondary amines III, whereby the substituents R and R are as above defined, using conditions and methods well known to those skilled in the art to prepare an amide from an amine and a carboxylic acid or a carboxylic acid derivative, using standard peptide coupling agents, such as e.g. DIC, EDC, TBTU, DECP, or others, to yield compounds of formula TV. Re-moval of the N-protecting group using the appropriate deprotection agents produces deriva-tives of formula V. These can be treated with acylating agents of general formula VI, whereby the substituent R1 is as above defined, while LG could be any appropriate leaving group. Preferred acylating agents VI are acid chlorides (Via), used in conjunction with a tertiary amine base, or carboxylic acids (Vlb), used in conjunction with a peptide coupling agent, e.g. from the above mentioned group, to yield the products of general formula I, with B being defined as C(O)Ν8R9 (la).
Scheme 1
II III IV
Via (e.g.,A=C(0);LG=CI) Vlb (e.g.,A=C(0);LG=OH) la
Other derivatives of formula I are prepared using known modifications to the Scheme 1 reaction sequence. Compounds of formula I wherein A is different from the carbonyl functionality are prepared by replacing formula VI compounds with compounds containing the appropriate functional groups, e.g. sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, substituted alkyl halides, or others to yield sulfonamide, urea, thiourea, carbamate, substituted alkyl derivatives, or others, respectively.
Compounds of formula II, whereby the substituent X is CR6R7, and R6 and R7 are as above defined, can be prepared from compoxmds of general formula VII by Wittig-type reactions with anions of phosphoranes such as Villa and/or of phosphonates such as Vlllb, followed by saponification of the ester function using standard synthetic techniques, as hereinafter described in the Examples and shown in Scheme 2.
Scheme 2
Compounds of general formula VII can be prepared from commercially available, suitably N- protected 4-hydroxyproline X, by a reaction sequence consisting of oxidation and esterification, using standard synthetic techniques as hereinafter described in the Examples and shown in Scheme 3.
Scheme 3
VII
Compounds of formula π, wherein the substituent X is NOR6 or NNR6R7, and R6 and R7 are as above defined, can be prepared from compounds of general formula XI by reaction with substituted hydroxyl amines Xlla and or substituted hydrazines and/or hydrazides Xllb using standard synthetic techniques as hereinafter described in the Examples and shown in Scheme 4.
Scheme 4
Xlla (X = N-0-R6)
XI Xllb (X = N-N-R6R7) II
Compoxmds of formula Xlla are commercially available or prepared by standard synthetic techniques as hereinafter described in the Examples. Compoxmds of formula II with X = S are accessible from the corresponding suitably protected ketopyrrolidine intermediates VII through standard functional group interconversion methods well known to the person skilled in the art, such as, e.g., by treatment with Lawesson's reagent or others (Pedersen, B. S. et al.; Bull. Soc. Chim. Belg. 1978, 87, 223), followed by saponification.
Accordmg to another process, pyrrolidine derivatives according to the general formula I, whereby the substituent B is a heterocyclic residue Bl as above defined, and the substituents are as above defined, are prepared from the corresponding suitably N-protected 4-substituted pyrrolidine derivatives II, whereby the substituent X is as above defined, by solution-phase chemistry protocols such as described in the Examples and shown in Scheme 5, below. The starting suitably N-protected 4-substituted pyrrolidine derivatives II are first reacted with ortho-substituted primary anilines of general formula XIII, whereby the substituents Q, Z, E, Y, and R11 are as above defined, using standard peptide coupling agents, such as DIC, EDC, TBTU, DECP, or others, followed by exposure to dilute weak acid, such as acetic acid, in a suitable organic solvent, such as DCM, to promote cyclisation yielding compounds of formula XIV. Removal of the N-protecting group using the appropriate deprotection agents produces cyclic derivatives of formula XV. These can be treated with acylating agents of general formula VI, whereby the substituent R1 is as above defined, while LG could be any appropriate leaving group. Preferred acylating agents VI are acid chlorides (Via), used in conjunction with a tertiary amine base, or carboxylic acids (Vlb), used in conjunction with a peptide coupling agent, e.g. from the abovementioned group, to yield the products of general formula I, with B being defined as Bl (lb).
Scheme 5
XIII XIV
Other derivatives of formula I are prepared using known modifications to the Scheme 5 reaction sequence. Compounds of formula I wherein A is different from the carbonyl functionality are prepared by replacing formula VI with compoxmds containing the appropriate functional groups, e.g. sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, substituted alkyl halides, or others to yield sulfonamide, urea, thiourea, carbamate, substituted alkyl derivatives, or others, respectively. According to another general process, summarized in Scheme 6, pyrrolidine derivatives according to the general formula I, whereby the substituents A, B, X, and R are as above defined, are prepared from compounds of formula XVI, using the synthetic techniques as outlined in Schemes 2 and 4. As fiirther shown in Scheme 6, compounds of formula XVI are accessible either from XI, following, e.g., the synthetic methodologies introduced in Schemes 1 and 5, or from Ic through hydrolysis of the methyloxime moiety, e.g. under mild hydrolysis conditions as described hereinafter in the Examples. This present synthetic strategy is most preferred when X is NOH or NNR6R7, whereby the substituents R6 and R7 are as above defined.
Scheme 6
Ic
According to yet another process, pyrrolidine derivatives according to the general formula I, whereby the substituents A, B, X, and R1 are as above defined, are prepared from the corresponding suitably N-protected 4-substituted pyrrolidine derivatives II, whereby the substituent X is above defined, by a solid-phase protocol such as described in the examples and shown in Scheme 7, below. The N-Boc-protected 4-substituted pyrrolidine derivative II is reacted e.g. with Kaiser oxime resin using standard carbodiimide-mediated coupling conditions well known to the practitioner skilled in the art, followed by Boc-deprotection with dilute TFA in DCM, or with BF3»OEt2 in dilute HOAc in DCM, to give compound XIX. The latter compoxmd can be treated with acylating agents of general formula VI, whereby the substituent R1 is as above defined, while LG could be any appropriate leaving group. Preferred acylating agents VI are acid chlorides (Via), used in conjxmction with a tertiary amine base, or carboxylic acids (Vlb), used in conjunction with a peptide coupling agent, e.g. DIC or EDC, to yield products of general formula XX.
Compoxmds of formula I wherem A is different from the carbonyl functionality are pre-pared by replacing formula VI with compounds containing the appropriate functional groups, e.g. sulfonyl chlorides, isocyanates, isothiocyanates, chloroformates, substituted alkyl halides, or others to yield sulfonamide, urea, thiourea, carbamate, substituted alkyl derivatives, or others respectively.
In order to obtain the final compounds of general formula I, the linkage to the resin is cleaved by prolonged treatment with amines of general formulae III or XIII and low percentages of a weak acid, such as HOAc. The cycles within the below Scheme 7 illustrate the resign beads to which the corresponding compounds are linked during the solid phase synthesis. Other derivatives of formula I are prepared using known modifications to, or variations of, the Scheme 7 reaction sequence. Further to the above mentioned Kaiser oxime resin, other suitable reagents, notably resins, known to a person skilled in the art, could be employed for the solid-phase synthesis of compounds of general formula I.
Scheme 7
XVII XVIII XIX
XIII
The reaction sequences outlined in the above Schemes provides enantiomerically pure compounds of formula I, if enantiomerically pure starting materials are used. (R) as well as (S) enantiomers can be obtained depending upon whether (R) or (S) forms of commercially available compounds of formulas II, III, VI, and/or X were used as the starting materials.
However, the reaction sequences outlined in the above Schemes usually provide mixtures of (E) and (Z) isomers with respect to the substituents on the exocyclic double bond of the pyrrolidine ring. In all cases studied, these (E)/(Z)-isomers could be separated by standard chromatography techniques well known to the person skilled in the art, such as by reversed phase high-pressure liquid chromatography (HPLC) or silica gel flash chromatography (FC). The assignment of the absolute configuration of the exocyclic double bond was performed using NMR-techniques well described in the literature as will be known to the practitioner skilled in the art (for configurationnal assignements of e.g. oxi e functio-nalities, see e.g. E. Breitmaier, W. Voelter Carbon-13 NMR Spectroscopy, 3rd Ed, VCH, 1987, p. 240).
Accordmg to a further general process, compounds of formula I can be converted to alternative compoxmds of formula I, employing suitable interconversion techniques such as hereinafter described in the Examples.
If the above set out general synthetic methods are not applicable for obtaining compounds according to formula I and/or necessary intermediates for the synthesis of compounds of formula I, suitable methods of preparation known by a person skilled on the art should be used. In general, the synthesis pathways for any individual compound of formula I will depend on the specific substitutents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art. For all the protection, de-protection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley-Interscience, 1991.
Compoxmds ofthis mvention can be isolated in association with solvent molecules by crystallization from evaporation of an appropriate solvent. The pharmaceutically acceptable acid addition salts of the compoxmds of formula I, which contain a basic center, may be prepared in a conventional manner. For example, a solution of the free base may be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts may be obtained in an analogous manner by treating a solution of compound of formula I with a suitable base. Both types of salt may be formed or interconverted using ion- exchange resin techniques.
If the above set out general synthetic methods are not applicable for the obtention of com- pounds of formula I, suitable methods of preparation known by a person skilled in the art should be used. A final aspect of the present invention is related to the use of the compounds according to formula I for the modulation of the Oxytocm receptor, the use of said compounds for the preparation of pharmaceutical compositions for the modulation of the oxytocin receptor as well as the formulations containing the active compoxmds according to formula I. Said modulation of the oxytocin receptor is viewed as a suitable approach for the treatment of preterm labor, premature birth and dysmenorrhea. Hence, the compoxmds od the present invention are suitable for the treatment of preterm labor, premature birth and dysmenorrhea.
When employed as pharmaceuticals, the pyrrolidine derivatives of the present mvention are typically administered in the form of a pharmaceutical composition. Hence, pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope of the present invention. A person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition. Also, the present invention provides compounds for use as a medicament. In particular, the invention provides the compounds of formula I for use as antagonists of the oxytocin receptor, for the treatment or prevention of disorders mediated by the oxytocin receptor in mammals, notably of humans, either alone or in combination with other medicaments, e.g. in combination with a further OT antagonist.
The compounds of the mvention, together with a conventionally employed adjuvant, car-rier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use). Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. When employed as pharmaceuticals, the pyrrolidine derivatives ofthis invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds ofthis invention are administered in a pharmaceutically effective amoimt. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
The pharmaceutical compositions of these inventions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds are preferably formulated as either injectable or oral compositions. The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for hximan subjects and other mammals, each unit containing a predeter-mined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the pyrrolidine compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As above mentioned, the pyrrolidine derivatives of formula I in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
The above described components for orally administered or injectable compositions are merely representative. Further materials as well as processing techniques and the like are set out in Part 8 of Remington 's Pharmaceutical Sciences, 17th Edition, 1985, Marck Publishing Company, Easton, Pennsylvania, which is incorporated herein be reference.
The compounds ofthis mvention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the incorporated materials in Remington 's Pharmaceutical Sciences.
In the following the present invention shall be illustrated by means of some examples which are not construed to be viewed as limiting the scope of the invention. The HPLC, NMR and MS data provided in the examples described below were obtained as followed. The following abbreviations are hereinafter used in the accompanying examples: min (minute), hr (hour), g (gram), mmol (millimole), m.p. (melting point), eq (equivalents), mL (milliliter), μL
(microliters), mL (milliliters), ACN (Acetonitrile), CDC13 (deuterated chloroform), cHex (Cyclohexanes), DCM (Dichloromethane), DECP (Diethylcyanophos-phonate), DIC (Diisopropyl carbodiimide), DMAP (4- Dimethylaminopyridine) DMF (Dimethylformamide), DMSO (Dimethylsulfoxide), DMSO- . (deuterated dimethylsul-foxide), EDC (l-(3-Dimethyl- aminopropyl)-3-ethylcarbodiimide), EtOAc (Ethyl acetate), Et2O (Diethyl ether), HOBt (1- Hydroxybenzotriazole), K2CO3 (potassium carbonate), NaH (Sodium hydride), NaHCO3 (Sodium bicarbonate), nBuLi (n Butyllithium), TBTU (O-Benzotriazolyl-N,N,N',N'- tetramethyluronium-tetrafluoroborate), TEA (Triethyl amine), TFA (Trifluoro-acetic acid), THF (Tetrahydrofuran), MgSO4 (Magnesium sulfate), PetEther (Petroleum ether), rt (room temperature).
Examples
Intermediate 1: (2S)-l-(tert-butoxycarbonyl)-4-oxo-2-ρyrrolidinecarboxylic acid
Commercial (2S,4R)-l-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid (30g, 0.13mol) was dissolved in acetone (1500ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. A freshly made solution of 8N chromic acid was prepared by dissolving chromium trioxide (66.7g, 0.667mol) in water (40ml), adding concentrated sulphuric acid (53.3ml) and adding enough water to bring the solution volume to 115ml. The 8N chromic acid solution (115ml) was then added dropwise over a period of 30 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of 25 °C by the use of an ice bath. After the complete addition of the chromic acid, the reac-tion mixture was stirred for a further 15 minutes - maintaining the optimal temperature of 25 °C. The reaction mixture was then quenched by the addition of methanol (20ml). Exotherm controlled by the use of an ice bath and, if necessary, direct addition of a small amount of crushed ice to the reaction mixture itself. The reaction mixture was filtered through a Celite pad and then concentrated in vacuo. The resulting acidic solution was then extracted with ethyl acetate (3x300ml) and the combined organic layers washed with brine (2x100ml). Organics then dried with magnesium sulfate and concentrated in vacuo. Crude product recrystallised from ethyl acetate to give the white crystalline product, (2S)-\-(tert- butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (22.55g, 76%). The antipodal intermediate, (2R)-l-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid, was made according to the same protocol, starting from commercial (2R,4S)-l-(tert-butoxycarbonyl)-4- hydroxy-2-pyrrolidinecarboxylic acid.
IH NMR (360MHz, CDC13); 1.4 (m, 9H), 2.5-3.0 (m, 2H), 3.7-3.9 (m, 2H), 4.75 (dd, IH) Intermediate 2: 1 -tert-butyl 2-methyl (2S)-4-oxo-1.2-pyrrolidinedicarboxylate.
A solution of (2S)-l-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid(lg, 4.3mmol) in a 1:1 mixture of methanol and toluene (60ml) was made. Trimethylsilyl diazomethane (6.5ml of a 2M solution in hexanes, 13mmol) was then added dropwise to the stirred solution at room temperature under nitrogen. After completion of the evolution of nitrogen gas, the resulting yellow solution was evaporated in vacuo, and the residue filtered through a pad of silica gel, eluting with ethyl acetate. Removal of solvent from the filtrate gave a yellow oil (1.05g, near quantitative yield).
1H NMR (400 MHz, CDC13); 1.4 (m, 9H), 2.5 (m, IH), 2.8-2.9 (m, IH) 3.7 (s, 3H), 3.9 (m, 2H), 4.6-4.8 (m, IH).
Intermediate 3: 1 -tert-butyl 2-methyl (2S,4EZ)-4-(chloromethylene -l,2-pyrrolidine- dicarboxylate
Chloromethyltriphenylphosphonium iodide (270mg, 0.62mmol) was added to a solution of potassium tert-butoxide (67mg, 0.59mmol) in anhydrous diethyl ether (5ml) under nitrogen and the resulting bright yellow mixture stirred for 30 minutes at ambient temperature. The reaction was then cooled to 0°C and a solution of 1 -tert-butyl 2-methyl (2S)-4-oxo-l,2- pyrrolidinedicarboxylate (lOOmg, 0.41mmol in 2ml anhydrous diethyl ether) was added dropwise. The reaction was then warmed to room temperature and stirred for 30 minutes before adding saturated aqueous ammonium chloride solution (0.5ml). The organic layer was removed in vacuo, and the aqueous washed with diethyl ether (3 x 5ml). The combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent. The desired product was isolated by silica gel chromatography, eluting with 15% ethyl acetate in hexanes to give 105mg (93% yield) as a off-white wax.
1H NMR (400 MHz, CDC13); 1.4 (9H, m), 2.6-2.75 (m, IH), 2.8-3.0 ( , IH), 3.65 (s, 3H), 4.1 (m, 2H), 4.4-4.5 (m, lH)5.9-6.0 (m, IH).
Intermediate 4: 1 -tert-butyl 2-methyl (2S)-4-methylene-l,2-pyrrolidinedicarboxylate Methyltriphenylphosphonium bromide (22g, 61.6mmol) was added to a solution of potassium tert-butoxide (6.5g, 57.6mmol) in anhydrous diethyl ether (450ml) at 0°C under nitrogen and the resulting bright yellow mixture stirred for 30 minutes. A solution of 1-tert-butyl 2-methyl (2S)-4-oxo-l,2-pyrrolidinedicarboxylate (lOg, 41.1mmol in 150ml anhydrous diethyl ether) was added slowly to the reaction mixture, which was then warmed at 35°C for 3h. Saturated aqueous ammonium chloride solution (0.5ml) was then added. The organic layer was removed, and the aqueous washed with diethyl ether (3 x 5ml). The combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent. Silica gel chromatography, eluting with 15% ethyl acetate in hexanes gave the desired pro-duct 6.9g (70% yield) as a off-white wax.
1H NMR (400 MHz, CDC13); 1.4 (9H, m), 2.5 (m, IH), 2.8 (m, IH), 3.65 (s, 3H), 4.0 (m, 2H), 4.3-4.5 (m, IH), 4.9 (m, 2H).
Intermediate 5: 1-tert-butyl 2-methyl (2S,4EZ)-4-(cyanomethylene')-1.2-pyrrolidme- dicarboxylate
Diethyl cyanomethyl phosphonate (0.86 ml, 4.4mmol) was dissolved in dry THF (50 ml) and the solution cooled to 0°C. Sodium hydride (205mg of a 60% suspension in parraf oil, 5.1 mmol) was then added cautiously and the reaction stirred for 30 min. The reaction mixture was then cooled to -78°C and a solution of 1-tert-butyl 2-methyl (2S)-4-oxo-l,2- pyrrolidinedicarboxylate (l.Og, 4.1mmol) in dry THF (5ml) was added dropwise. The reaction was then allowed to reach room temperature. Saturated aqueous ammonium chloride solution (15ml) was then added, followed by ethyl acetate (100ml). (The organic layer was removed, and the aqueous washed with ethyl acetate (3 x 5ml). The combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent. Silica gel chromatography, eluting with 35% ethyl acetate in hexanes gave the desired compound (860mg, 80%) as an off-white wax.
1H NMR (360 MHz, CDC13); 1.4 (m, 9H), 2.7-3.0 (m, IH), 3.1-3.3 (m, IH), 3.7 (m, 3H), 4.2- 4.4 (m, 2H), 4.5-4.7 (m, IH), 5.4 (m, IH). Intermediate 6: 1-tert-butyl 2-methyl (2S,4EZ -4-benzylidene-1.2-pyrrolidinedicarboxylate
Potassium tert-butoxide (6.1g, 54mmol) was added portionwise to a solution of benzyl- triphenylphosphonium chloride (22.45g, 58mmol) in anhydrous dichloromethane (400ml) and the reaction stirred at ambient temperature for lh. The solution was then cooled to 0°C and a solution of 1-tert-butyl 2-methyl (2S)-4-oxo-l ,2-pyrrolidinedicarboxylate (9.36g, 38.5mmol) in dry dichloromethane (30ml) was added dropwise. After stirring for a further lh at 0°C the reaction was stirred for a further 3h at ambient temperature. Saturated aqueous ammonium chloride solution (30ml) was then added. The organic layer was removed, and the aqueous washed with dichloromethane (3 x 20ml). The combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent. Silica gel chromato-graphy, eluting with 30% ether in hexanes gave the desired product 8.65g (71% yield) as a pale yellow wax.
1H NMR (400 MHz, CDC13);1.5 (m, 9H), 2.8-3.0 (m, IH), 3.2 (m, IH), 3.7 (m, 3H), 4.2-4.4 (m, 2H), 4.5-4.6 (m, IH), 6.3-6.4 (m, IH), 7.1-7.5 (m, 5H).
Intermediate 7: (2SAEZ)-1 -('tert-butoxycarbonyl -4-(methoxyimmo)-2-pyrrolidme-carboxylic acid
A solution was made containing (2S)-l-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0g, 21mmol) and O-methylhydroxylamine hydrochloride (2.7g, 32.8mmol) in chloroform (100ml) containing triethyl-amine (5.5g, 55mmol). The reaction mixture was then stirred at ambient temperature over-night, prior to removal of solvent. The resultant crude reaction mixture was dissolved in ethyl acetate (150ml) and washed rapidly with IN HCl (40ml). The acidic layer was then extracted with ethyl acetate (3 x 20ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.3g, 94%) was isolated as a pale yellow oil.
1H NMR (400 MHz, CDC13); 1.45 (m, 9H), 2.8-3.2 (m, 2H), 3.9 (s, 3H), 4.2 (m, 2H), 4.5-4.7 (m, IH). Intermediate 8: (2S,4EZ)-l-("tert-butoxycarbonyl)-4-(ethoxyimmo)-2-pyrrolidmecarboxylic acid
A solution was made containing (2S)-l-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidine-carboxylic acid (5.0g, 22mmol) and O-ethylhydroxylamine hydrochloride (6.4g, 65.5mmol) in a 1:1 mixture of pyridine and ethanol (100ml). The reaction was heated to reflux for 2.5h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40ml). The acidic layer was then extracted with ethyl acetate (3 x 20ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.5g, 93%) was isolated as a pale yellow oil.
1H NMR (400 MHz, DMSO); 1.3 (t, 3H), 1.55 (m, 9H), 2.9-2.7 (m, IH), 3.4-3.1 (m, IH), 4.1- 4.3 (m, 4H), 4.6 (m, IH), 12-13.5 (br, IH).
Intermediate 9: 2S,4EZ)-4-[("allyloxy)imino"|- 1 -ftert-butoxycarbonylV2-pyrrolidine- carboxylic acid
A solution was made containing (2S)- 1 -(tert-butoxycarbonyl)-4-oxo-2-pyrrolidine-carboxylic acid (5.0g, 22mmol) and O-allylhydroxylamine hydrochloride monohydrate (7.2g, 65.5mmol) in a 1:1 mixture of pyridine and ethanol (100ml). The reaction was heated to reflux for 2.5h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40ml). The acidic layer was then extracted with ethyl acetate (3 x 20ml) and the combined organic layers washed with brine before drying over magnesium sulfate, filtering and re-moval of solvent in vacuo. The desired product (5.9g, 94%) was isolated as a pale yellow oil.
1H MR (400 MHz, CDC13); 1.5 (m, 9H), 2.8-3.2 (m, 2H), 4.2 (m, 2H), 4.5-4.7 (m, 3H), 5.25 (m, 2H), 5.9 (m, IH), 11.1 (broad S, IH).
Intermediate 10: l-["(aminooxy methyll-4-methoxybenzene A solution was made of Boc hydroxylamine (2.0g, 17.1mmol) in dry THF (60ml). Sodium hydride (l.lg of a 60% suspension in paraffin oil, 25.7mmol) was then added and the suspension stirred. A catalytic amoimt of KI was then added to the reaction prior to the cautious addition of 4-methoxybenzyl chloride (3.2g, 20.4mmol). The reaction was then allowed to stir overnight before removal of solvent in vacuo. The residue was taken up with diethyl ether (100ml) and HCl gas bubbled in for 20 minutes, causmg the start of precipitation of the product. The flask was stoppered and left to stand overnight. The product was then filtered off as a off-white wax (39-52% yield according to varying batches).
1H NMR (400 MHz, D2O);3.8 (s, 3H), 5 (s, 2H), 7.0 (d, 2H), 7.4 (d, 2H).
Intermediate 11 : (2S,4EZ)-l-(tert-butoxycarbonyl)-4-{[('4-methoxybenzyl)oxy'|imino>-2- pyrrolidine-carboxylic acid
The same method as employed in the preparation of Intermediate 7, but starting from (2S)-1- (tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1- [(aminooxy)methyl]-4-methoxy-benzene (Intermediate 10) gave the title compoxmd as a gum in a 85% yield.
1H NMR (400 MHz, DMSO); 1.5 (m, 9H), 2.7-2.9 (m, IH) 3.9 (s, 3H), 4.2 (m, 3H), 4.6 (m, IH), 5.15 (s, 2H), 7.1 (d, 2H), 7.45 (d, 2H).
Intermediate 12: 2-aminoethyl acetate, TFA-salt
A solution was made containing ethanolamine (36.5ml, 0.6mol) in chloroform (1000ml). The Boc2O (13.1g, 60mmol) dissolved in chloroform (600ml) was slowly added dropwise at 0°C over a 6-hours period (the temperature was maintained all over this period). The reaction was allowed to reach room temperature and was stirred overnight. The organic layer was washed with water (2x500ml), brine and dried over magnesium sulfate before being concentrated in vacuo. The desired product (9.5g, >95%) was isolated as a colourless oil and was used without further purification. A solution was made containing the Boc-ethanolamine (1.92g, 12mmol) with potassium carbonate (5g, 36mmol) in DCM (40ml). Acetyl chloride (30ml, 0.42mol) was added and the reaction stirred for 6 hours at room temperature. The excess of acetyl chloride was removed in vacuo and the crude dissolved in DCM(lQOml). The organic layer was washed with water (50ml), brine and dried over magnesium sulfate before being concentrated ■ in vacuo. The desired product (1.86g, 77%) was isolated as a colourless oil and was used without further purification. A solution was made containing the O-acyl, Boc-ethanolamine (1.65g, δ.lmmol) in DCM (20ml) and TFA (20ml) was added. After one hour at room temperature, the solvent was removed in vacuo. The crude was concentrated from methanol (2-3 times) and from DCM (2-3 times) to give the expected compound (1.75g, quant.) as an oil used without further purification.
1H NMR (400 MHz, D2O); 2.0 (m, 9H), 3.1-3.2 (m, 2H), 4.15-4.25 (m, 2H).
Intermediate 13: 2'-methyl 1,1 '-biphenyl] -4-carboxylic acid
To a mixture of 4-bromobenzoic acid (30g, 0.15mol), 2-methylphenylboronic acid (24g, 0.15 mol), sodium carbonate (250g) in toluene (500mL) and water (500mL) was added tetrakis- triphenylphosphine palladium(O) (9g, 0.0074mol) under nitrogen atmosphere. The reaction mixture was refluxed for lOh. After this time, 100ml of 10% NaOH were added to the reaction mixture, the aqueous layer was separated and washed with toluene (2x200mL). Acidification of the aqueous layer with 3NΗC1 solution gave a solid product, which was filtered, washed with water and dried. The crude product was then crystallised from toluene to yield 2'- methyl[l,l'-biphenyl]-4-carboxylic acid (20g, 62.5%). Conversely, the product could also be obtained from l-bromo-2-methylbenzene and 4-carboxybenzeneboronic acid, using analogous conditions.
1H NMR (300 MHz, DMSO); 2.2 (s, 3H), 7.2-7.4 (m, 4H), 7.43 (d, J = 9Hz, 2H) , 7.99 (d, J = 9Hz, 2H), 13 (b, IH).
Similarly, using the appropriate commercial boronic acids and arylbromides, the following, related 1,1' -biphenyl intermediates 13 may be obtained: 4'-methyl[l,l'-biphenyl]-4-carboxylic acid; 2',3-dimethyl[l,r-biphenyl]-4-carboxylic acid; 2',6'-dimethyl[l,r-biphenyl]-4-carboxylic acid; 2-methyl[l,l'-biphenyl]-4-carboxylic acid; 3- methyl[l,r-biphenyl]-4-carboxylic acid; 2,2'-dimethyl[l,r-biphenyl]-4-carboxylic acid; 2'- methoxy[l,r-biphenyl]-4-carboxylic acid; 3 '-methoxy [l,r-biphenyl]-4-carboxylic acid; 4'- methoxy[l,r-biphenyl]-4-carboxylic acid; 2'-chloro[l, -biphenyl]-4-carboxylic acid; 3'- chloro[l,l'-biphenyl]-4-carboxylic acid; 4'-chloro[l,l'-biphenyl]-4-carboxylic acid; 3',4'- dichloro[ 1 , 1 -biphenyl] -4-carboxylic acid; 2'-(trifluoromethyl)[ 1 , 1 '-biphenyl] -4-carboxylic acid; 3'-(trifluoromethyl)[l,r-biρhenyl]-4-carboxylic acid; 2'-cyano[l,l'-biphenyl]-4- carboxylic acid; 2',4'-difluoro[l,r-biphenyl]-4-carboxylic acid; 4-(2-pyridinyl)benzoic acid; 4-(3-pyridinyl)benzoic acid; 4-(4-pyridinyl)benzoic acid; 4-(5-pyrimidinyl)benzoic acid.
Intermediate 14: 4-(3-methyl-2-pyridinyl benzoic acid
A mixture of 2-bromo-3-methylpyridine (22.5g, 0.1312mol), 4-(hydroxymethyl)phenyl- boronic acid (25g, 0.164mol), Pd(PPh3)4 (9.5g, 0.0082mol), and sodium carbonate (200g in 500 ml of water) in toluene (750 ml) were refluxed under nitrogen atmosphere for 15h. Separated the toluene layer and distilled under reduced pressure to give a residue. The residue was then purified by column chromatography to yield [4-(3-methyl-2-ρyridinyl)- ρhenyl]methanol (12g, 47%).
To a solution of [4-(3-methyl-2-pyridinyl)phenyl]methanol (12g, 0.06mol) in dry DMF (150mL) was added pyridiniumdichromate (91g, 0.24mol) and stirred at RT for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate (250mL). The organic layer was washed with water, brine, dried and concentrated. The crude was purified by colximn chromatography over silica gel to give 4-(3-methyl-2-pyridinyl)benzoic acid (3g, 25%) as white solid.
1H NMR (300 MHz, DMSO); 2.3 (s, 3H), 7.33 (dd, J = 7.5Hz, 5Hz, IH), 7.67 (d, J = 8Hz, 2H) , 7.75 (d, J = 7.5Hz, IH), 8.01 (d, J = 8Hz, 2H), 8.50 (d, J = 5Hz, IH), 13 (b, IH).
Intermediate 15: 4-(l-oxido-3-pyridinyl benzoic acid To amixture of 4-tolylboronic acid (38g, 0.28mol), 3-bromopyridine (44g, 0.28mol), Na2CO3 (200g) in toluene (500ml) and water (500ml) was added Pd(PPh3) (16g, O.O mol), and refluxed for 16h. The reaction mixture was cooled, and the separated organic layer was washed with water and brine, and dried. The solvent was removed to give 4-(3-pyridyl)toluene (42g, 90%).
To a mixture of 4-(3-pyridyl)toluene (35g, 0.207mol) in pyridine (400ml) and water (400ml) was added KMnO (163g, 1.03mol) in portions and refluxed for 12h. The reaction mixture was filtered through celite and acidified with cone. HCl. The product was washed with water and dried to give 4-(3-pyridyl)benzoic acid (32g, 76%) as a white solid. To amixture of 4-(3- ρyridyl)benzoic acid (22g, 0.1 lmol) in THF (2.51), mCPBA (152g, 0.44mol, 50%) was added and stirred at RT for 12h. The solid was filtered, and washed with THF to give 4-(l-oxido-3- pyridinyl)benzoic acid (20g, 86%).
1H NMR (300 MHz, DMSO); 7.5-7.8 ( , 5H), 7.9 (d, J = 8Hz, 2H) , 8.33 (d, J = 5Hz, 2H).
Similarly, starting from 4-tolylboronic acid (45g, 0.33mol) and 2-bromopyridine (52g, 0.33mol), the related intermediate 4-(l-oxido-2-pyridinyl)benzoic acid was obtained.
Example 1: General procedure for the saponification of the olefin-type proline methyl esters, such as Intermediates 3-6.
A solution of sodium hydroxide (4.5g, 112mmol) in water (70ml) was added to the relevant proline olefin methyl ester (66mmol) in 3:1 dioxane:water (500ml) and the reaction stiπed for 3h. The reaction mixture was then washed with diethyl ether (2 x 50ml), and the aque-ous phase acidified to pH 2 (0.1N HCl) and extracted into ethyl acetate. The ethyl acetate layer was then dried over magnesium sulfate, filtered and the solvent was then removed in vacuo to give the desired product in near quantitative yields as an oil which was used without further purification. Example 2: General protocol for the solution-phase synthesis of oximether pyrrolidine derivatives of general formula la (Scheme 1):
Method A: e.g. (2S,4EZ)-l-Cf l'-biρhenyll-4-ylcarbonyl)-N-C2-methoxyethyl)-4- (methoxyimino)-2-pyπolidinecarboxamide
a) Protocol for the formation of the amide bond
A solution was made containing the central building block, e.g. (2S,4EZ)-l-(tert-butoxycar- bonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid (Intermediate 7) (1.5g, 5.8mmol), an amine or an amine salt, e.g. 2-methoxy-ethylamine (0.51ml, 5.81mmol) and DMAP (780mg, 5.8mmol) in DCM (30 ml). At 0°C, ΕDC (l.lg, 5.8mmol) was slowly added portion-wise. The reaction was slowly allowed to reach room temperature and was stirred overnight. The DCM was evaporated and the crude purified by column chromatography using ΕtOAc (100%) to collect the desired product, e.g. tert-butyl (2S,4EZ)-2-{[(2-meth-oxyethyl)amino]carbonyl}-4- (methoxyimino)-l-pyπolidmecarboxylate (1.5g, 80%) as a colourless oil.
1H NMR (400 MHz, CDC13); 1.25 (m, 9H), 2.5-2.9 (m, 2H), 3.1 (s, 3H), 3.2-3.3 (m, 4H), 3.65 (s, 3H), 3.8-4.4 (m, 3H), 6.7 (s broad, IH).
b) Protocol for the N-deprotection step
A solution was made containing the amide compounds from the previous step, e.g. tert-butyl (2S,4EZ)-2-{[(2-methoxyethyl)ammo]carbonyl}-4-(methoxyimino)-l-pyrrolidine-carboxylate (1.5g, 0.4 mmol), in anhydrous ether (35ml). HCl gas was bubbled slowly through the reaction and the deprotection was followed by TLC. After approximately 20 minutes, the ether was evaporated. The product was concentrated in vacuo from DCM (2-3 times) to remove the HCl. The desired product, e.g. (2S,4EZ)-N-(2-methoxyethyl)-4-(methoxyimino)-2- pyπolidinecarboxamide (1.2g, quant.) was isolated as a yellow oil and used without further purification.
c) Protocol for the N-capping step A solution was made containing the free NH-compoxmd from the previous step, e.g. (2S,4EZ)- N-(2-methoxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide (940mg, 3.7 mmol), a carboxylic acid, e.g. [l,l'-biphenyl]-4-carboxylic acid (740mg, 3.7mmol) and DMAP (960mg, 7.8mmol) in DCM (30 ml). At 0°C, ΕDC (715mg, 3.7mmol) was slowly added portionwise. The reaction was slowly allowed to reach room temperature and was stirred overnight. The DCM was evaporated and the crude purified by column chromato-graphy using ΕtOAc (100%) to collect the desired product, e.g. (2S,4EZ)-l-([l,l'-biρhe-nyl]-4-ylcarbonyl)-N-(2- methoxyethyl)-4-(methoxyimino)-2-pyπolidinecarboxamide as a mixture of two isomers as an off-white solid.
IH ΝMR (400 MHz, CDC13); 2.75-2.85 (m, IH), 3.1-3.3 (m, 4H), 3.4-3.5 (m, 4H), 3.8 (m, 3H), 4.1-4.3 (m, 2H), 5.1 (m, IH), 6.9 (m, IH), 7.2-7.7 (m, 10H). M^APCl ); 396.
Method B: e.g. (2S.4E and 4Z)-N-r(2S)-2-hvdroxy-2-τ>henylethyl]-4-(methoxyimino)-l-r(2'- methyl[ 1 , 1 '-biphenyl] -4-yl carbonyl1 -2-p yrrolidinecarboxamide
a) Protocol for the formation of the amide bond
To a solution of the central building block, e.g. (2S,4EZ)-l-(tert-butoxycarbonyl)-4-
(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 7) (24.2 mmol, 6.24 g) in dry THF (125 ml) at -25°C was added ΝMM (2.5 eq, 60.4 mmol, 6.64 ml) followed by isobutylchloroformate (1.05 eq, 25.4 mmol, 3.3 ml). The resulting mixture was stkred at - 25°C for 30 min and an amine or an amine salt, e.g. (S)-2-amino-l-phenylethanol (1.51 eq, 36.5 mmol, 5 g) was then added. The mixture was allowed to gradually warm to rt. After 16h, the solvents were removed. The residue was dissolved in AcOΕt, washed twice with ΝH4C1 saturated solution, then twice with 10% NaHCO3 solution. The organic layer was dried over Na2SO4, filtrated and concentrated to afford the desired product, e.g. tert-butyl (2S,4EZ)-2- ({[(2S)-2-hydroxy-2-phenylethyl]ammo}carbonyl)-4-(methoxyimino)-l-pyrrolidine- carboxylate (8.76 g, 96%) as a pale yellow oil in 88.5 % purity by HPLC. 1H NMR (CDC13: 300 MHz) δ 1.44 (s, 9H, N-5σc), 3.23-2.85 (m, 4H), 3.72 (m, IH), 3.85 (s, 3H, O-CH_), 4.10 (m, 2H), 4.49 (m, IH), 4.83 (m, IH), 7.34 (m, 5H, Ar-H); [M+Na+] (ESf): 400.
b) Protocol for the N-deprotection step
A solution was made containing the amide compounds from the previous step, e.g. tert-butyl (2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimmo)-l- pyπolidinecarboxylate (2.64 g, 7 mmol), in anhydrous DCM (35 ml). At 0°C, ΗC1 gas was bubbled slowly through the reaction and the deprotection was followed by TLC. After approximately 20 minutes, the DCM was evaporated. The product was concentrated in vacuo from DCM (2-3 times) to remove the ΗC1. The desired product, e.g. (2S,4EZ)-N-[(2S)-2- hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide (1.94 g, quant.) was isolated as a yellow solid and used without further purification.
c) Protocol for the N-capping step
To a suspension of 4-(2-methylρhenyl)benzoic acid (1.49 g, 7 mmol.) in 35 ml DCM, was added oxalyl chloride and DMF (3 ml) under ice cooling. The mixture was stiπed for 2h at rt. The solvent was removed affording the coπesponding acyl chloride as a yellow solid. It was dissolved in DCM (30 mL) and added slowly on a 0°C solution containing the free ΝΗ- compound from the previous step, e.g. (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-ρyrrolidinecarboxamide (1.94 g, 7 mmol), and triethylamine (5eq, 35 mmol, 4.9 ml) in dry DCM (35 ml). The reaction mixture was stiπed overnight at r.t.. Pol- trisamine was added (2.12 g, 3.45 mmol/g) in order to scavenge excess of acyl chloride. The mixture was shaken 3 h, filtered and the resulting solution was washed with ΝΗ CI sat, brine, and dried over Na2SO . After filtration and evaporation of the solvents, the resulting dark oil (3.26 g) was purified by flash chromatography (Biotage system, column 40M, 90 g SiO2, with gradients of DCM and MeOH as eluent), affording (2S,4EZ)-N-[(2S)-2-hydroxy-2- phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l, -biphenyl]-4-yl)carbonyl]-2- pyπolidinecarboxamide. Separation of the E/Z-isomers was achieved by several chromatographies, affording (2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l - [(2'-methyl[l,r-biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide (230 mg, colorless powder, 98.7% purity by HPLC) and (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-l-[(2'-methyl[l, -biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide (266 mg, colorless powder, 98.3 % purity by HPLC).
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]-4- yl)carbonyl]-2-pyπolidinecarboxamide: M.p. 74°C; IR (neat) v 3318, 2932, 1613, 1538, 1416, 1239, 1047, 848 cm-1; 1H ΝMR (300 MHz, CDC13): 2.27 (s, 3H, ArCH5), 2.89 (dd, J= 6, 12 Ηz, 1Η), 3.18 (br d, J= 12 Ηz, 1Η), 3.27 (m, 1Η), 3.76 (m, 1Η), 3.88 (s, 3Η, ΝOCH,), 4.28 (d, J= 10 Ηz, 1Η), 4.47 (d, J= 10 Ηz, 1Η), 4.59 (br s, 1Η), 4.88 (m, 1Η), 5.20 (m, 1Η), 7.03-7.42 (m, 11Η, Η arom.), 7.45-7.54 (m, 2Η, H arom.); M+(APCI ): 472; MXAPCT): 470. Analysis calculated for C28H29Ν3O4 0.3 H2O: C, 70.51; H, 6.26; N, 8.81. Found: C, 70.53; H, 6.30; N, 8.87.
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]-4- yl)carbonyl]-2-pyπolidinecarboxamide: M.p. 78°C; IR (neat) v 3318, 2938, 1622, 1538, 1416, 1233, 1045, 852 cm"1; 1H ΝMR (300 MHz, CDC13): 2.28 (s, 3H, ArCH3), 2.69 (dd, J= 6, 10 Ηz, 1Η), 3.02-3.22 (m, 2Η), 3.25 (br s, IH), 3.60 (m, IH), 3.86 (s, 3H, ΝOCH_), 4.14 (m, 2Η), 4.71 (m, IH), 4.96 (m, IH), 7.03-7.42 (m, 11H, H arom.), 7.45-7.54 (m, 2H, H arom.); M+(APCI+): 472; M"(APCr): 470. Analysis calculated for C28H29N3O4 0.9 H2O: C, 68.95; H, 6.36; N, 8.61. Found: C, 68.87; H, 6.25; N, 8.77.
d) E/Z-isomerisation
The pure E-isomer was isomerized to a mixture of the E/Z-isomers by the following procedure: the E-isomer was dissolved in dioxane/water 3:1 mixture. NaOH (1.7 eq; 0.52 mL of NaOH 1.6N) was added and the resultmg solution was stiπed 2 h at r.t. The mixture was neutralised with HCl 0.1 N and lyophilised. The components of the resulting E/Z-mixture were separated and purified by flash chromatography using same conditions as described above. Example 3: f2S.4EZ -l-(ri.l'-biphenyl1-4-ylcarbonylVN-r2-(diethylamino>ethyl1-4-{|'(4- methoχybenzyl oxy]imino}-2-pyπolidinecarboxamide
Following the general method as outlined in Example 2, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, [1,1 '- biphenyl] -4-carboxylic acid, and Ν1 ,ΝJ -diethyl- 1 ,2-ethanediamine the title compoxmd was obtained after column chromatography as an off-white solid as a mixture of Ε/Z-isomers.
IH NMR (400 MHz, CDC13); 1.05-1.15 (m, 6H), 2.7-2.8 (m, IH), 2.9-3.2 (m, 6H), 3.4 (m, IH), 3.6 (s, 3H), 4.0-4.1 (m, IH), 4.3-4.4 (m, IH), 3.75 (m, IH), 3.8 (m, 2H), 6.65 (m, 2H), 7.0-7.1 ( , 2H), 7.2-7.3 (m, 3H), 7.35-7.45 (m, 6H), 8.8 (s/br, 0.5H). ^(APCf); 543.
Example 4: r2S.4EZ)-l-Cri.r-biτ>henyl]-4-ylcarbonyn-4-(chloromethylene -N-r(2RS)-2- hydroxy-2-ρhenethyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 2, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, [ 1,1' -biphenyl] -4- carboxylic acid, and (li?S)-2-amino-l-phenylethanol, the title compoxmd was obtained after column chromatography as a mixture of E/Z-isomers as an off-white solid. The two isomers could be separated by another flash chromatographic purification step.
(2S,4E)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2i?S)-2-hydroxy-2- phenethyl]-2-pyrrolidinecarboxamide: IH ΝMR (400 MHz, CDC13); 2.6-2.7 (m, IH), 2.8-3.0 (m, 3H), 3.2 (m, IH), 3.4-3.6 (m, IH), 3.9 (m, IH), 4.15 (t, IH), 4.6 (m, IH), 4.85 ( , IH), 5.75 (s, IH), 7.0-7.4 (m, 14H). M+(APC ); 461.
(2S,4Z)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-[(2RS)-2-hydroxy-2- phenethyl]-2-pyπolidinecarboxamide: IH ΝMR (400 MHz, CDC13); 2.5-2.6 (m, IH), 2.7-2.9 (m, IH), 3.0 (m, IH), 3.1-3.4 (m, IH), 3.4-3.6 (m, IH), 3.9-4.0 (m, IH), 4.2-4.4 (m, 2H), 4.6 (m, IH), 4.8-4.9 (m, IH), 5.75 (s, IH), 7.0-7.5 (m, 14H). M+(APC1+); 461.
Example 5: f2S.4EZ)-N-r2-fdiethylamino)ethyl]-l -(diphenylacetylV4-(methoχyimmoV2- pyπolidinecarboxamide Following the general method as outlined in Example 2, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, diphenylacetic acid, and ^N1 -diethyl- 1,2-ethanediamine the title compound was obtained after column chromatography as an off-white solid as amixture of Ε/Z-isomers.
IHNMR (400 MHz, CDC13); 0.9 (t, 3H), 1.0 (m, 3H), 2.6-3.1 (m, 7H), 3.15 (m, IH), 3.4 (m, IH), 3.75 (s, 3H), 3.95 (t, IH), 4.4-4.7 (m, 4H), 5.1 (m, IH), 7.0-7.3 (m, 10H), 9.1 (m, IH). M+(APC ); 451.
Example 6: (2S.4EZ)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-l -(ρhenoxyacetylV2- pyπolidinecarboxamide
Following the general method as outlined in Example 2, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, phenoxyacetic acid, and 9- ethyl-9Η-carbazol-3-amine the title compound was obtained after column chromatography as an off-white solid as a mixture of Ε/Z-isomers. The isomers were then separated using column chromatography.
(2S,4E)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-l-(phenoxyacetyl)-2-pyπolidine- carboxamide: 1Η ΝMR (360MΗz, CDC13); 1.2 (m, 6H), 2.7 (m, IH), 3.35 (d, IH), 4.1 (m, 4H), 4.3 (d, IH), 4.45 (d, IH), 4.7 (m, 2H), 5.15 (d, IH), 6.9-7.3 (m, 10H), 7.9 (d, IH), 8.15 (m, IH), 9.0 (br s, IH). M+(APC ); 499.
(2S,4Z)-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-l-(ρhenoxyacetyl)-2-ρyπolidine- carboxamide: 1Η ΝMR (360MΗz, CDC13); 1.2 (m, 6H), 2.7 (m, IH), 3.2 (m, IH), 4.1 (m, 4H), 4.35 (m, 2H), 4.7 (m, 2H), 5.1 (m, IH), 6.9-7.3 (m, 10H), 7.9 (d, IH), 8.15 (m, IH), 9.0 (br s, IH). M+(APCI ); 499.
Example 7: (2S.4EZ)-N-f9-ethyl-9H-carbazol-3-vn-4-(methoxyimino)-l-rr2-oxo-6-pentyl-2H- pyran-3-yl)carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 2, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compoxmd was obtained after column chromatography as an off-white solid as a mixture of E/Z-isomers. The iso-mers were separated by column chromatography.
(2S,4E)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-l-[(2-oxo-6-ρentyl-2H-ρyran-3- yl)carbonyl]-2-pyπolidinecarboxamide: 1Η NMR (360MΗz, CDC13); 0.8 (m, 6H), 1.2 (m. 6H), 2.5 (m, 2H), 3.0 (m, IH), 3.3 (m, IH), 3.8 (s, 3H), 4.2 (m, 3H), 4.45 (m, IH), 5.3 (m, IH), 6.1 (d, IH), 7.1 (m, IH), 7.2 (m, IH), 7.3 (d, IH), 7.35 (m, l.H), 7.55 (m, IH), 7.65 (m, IH), 8.0 (d, IH), 8.5 (m, IH), 9.1 (br S, IH). M^ΕS "); 543.
(2S,4Z)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino)-l-[(2-oxo-6-ρentyl-2H-pyran-3- yl)carbonyl]-2-pyπolidinecarboxamide: 1Η ΝMR (360MΗz, CDC13); 0.8 (m, 6H), 1.2 (m. 6H), 2.5 (m, 2H), 3.05 (m, IH), 3.25 (m, IH), 3.75 (s, 3H), 4.1 (m, 3H), 4.45 (d, IH), 5.3 (d, IH), 6.1 (d, IH), 7.1 (t, IH), 7.2 (m, IH), 7.3 (m, IH), 7.4 (m, IH), 7.6 (m, IH), 7.7 (m, IH), 8.0 (d, IH), 8.45 (m, IH), 9.1 (m, IH). M^ΕS*); 543.
Example 8: ^S^EZ^^-frallyloxy minol-l-benzoyl-N-Cg-ethyl-gH-carbazol-S-vn-Σ- pyπolidinecarboxamide
Following the general method as outlined in Example 2, starting from (2S,4EZ)-4-[(allyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, benzoic acid, and 9-ethyl- 9Η-carbazol-3-amine the title compoxmd was obtained after column chromatography as an off- white solid as a mixture of Ε/Z-isomers.
IH ΝMR (360MHz, CDC13); 1.2 (m, 3H), 2.8 (m, IH), 3.35 (m, IH), 4.2 (m, 4H), 4.4 (m, 3H), 5.2 (m, 2H), 5.35 (m, IH), 5.85 (m, IH), 7.0-7.5 (m, 5H), 7.9 (m, 3H), 8.1 (m, 2H), 8.3 (m, IH), 9.2 (br s, IH). M^APCI*); 481.
Example 9: General protocol for the solution-phase synthesis of oximether pyrrolidine derivatives of general formula I containing additional reactive groups; (2SAEZ)-\-(\\,Y- biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl -4-rmethoxyimino -2-pyπolidinecarboxamide
a) Protocol for the formation of the amide bond A solution was made containing the central building block, e.g. (2S,4EZ)-l-(ter/-butoxycar- bonyl)-4-(methoxyimino)-2-ρyrrolidinecarboxylic acid (Intermediate 7) (575mg, 2.2mmol), the amine or amine salt containing the suitably protected reactive group, e.g. 2-ammoethyl acetate (Intermediate 12) (480mg, 2.2mmol) and DMAP (870mg, 7.1mmol) in DCM (20 ml). At 0°C, ΕDC (427mg, 2.2mmol) was slowly added portion-wise. The reaction was slowly allowed to reach room temperature and was stirred overnight. The DCM was eva-porated and the crude purified by column chromatography using ΕtOAc/Hexane: 55/45 to collect the desired amide compound, e.g. tert-butyl (2S,4EZ)-2-({[2-(acetyloxy)ethyl] -amino} carbonyl)- 4-(methoxyimino)-l-pyπolidinecarboxylate (373mg, 49%) as an oil.
IH NMR (400 MHz, CDC13); 1.7 (m, 9H), 2.1-2.2 (m, 3H), 2.8-3.3 (m, 2H), 3.7-3.8 (m, 2H), 4.0-4.1 (m, 3H), 4.2-4.8 (m, 5H), 7.3 (s broad, IH).
b) Protocol for the N-deprotection step
A solution was made containing the Boc-protected compound from the previous step, e.g. tert- butyl (2S,4EZ)-2-({[2-(acetyloxy)ethyl]amino}carbonyl)-4-(methoxyimino)-l-pyrroli- dinecarboxylate (373mg, 1.2mmol) in anhydrous ether (40ml). HCl gas was bubbled slowly through the reaction and the deprotection was followed by TLC. After approximately 20 minutes, the ether was evaporated. The product was concentrated in vacuo from DCM (2-3 times) to remove the HCl. The desired free NH product, e.g. 2-({[(2S,4EZ)-4-(methoxy- imino)pyπolidinyl]carbonyl}amino)ethyl acetate (300mg, quant.) was isolated as a yellow oil and used without further purification.
IH NMR (400 MHz, D2O); 1.75 (s, 3H), 2.55-2.65 (m, IH), 2.8-3.3 (m, 3H), 3.45-3.55 (m, 3H), 3.8-4.0 (m, 4H), 4.25-4.35 (m, IH).
c) Protocol for the N-cαpping step
A solution was made containing the amine-hydrochloride from the previous step, e.g. 2- ({[(2S,4EZ)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl acetate (560mg, 2mmol) and an acid chloride, e.g. [1,1 '-biphenyl] -4-carbonyl chloride (433mg, 2mmol) in DCM (20ml). Triethylamine (0.7ml, 5__ιmol) was added and the reaction stiπed overnight at room temperature. The DCM was evaporated and the crude purified by column chromatography using EtOAc (100%) to collect the desired amide compound, e.g. 2-({[(2S,4EZ)-l-([l,l'- biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyπolidinyl]carbonyl} amino)ethyl acetate (457mg, 54%) as an oil.
IH NMR (400 MHz, CDC13); 1.9 (s, 3H), 2.7-2.8 (m, IH), 3.2-3.6 (m, 3H), 3.75-3.85 (m, 3H), 4.0-4.4 (m, 4H), 5.15-5.25 (m, IH), 7.2-7.6 (m, 9H).
d) Protocol for the deprotection of the reactive group
A solution was made containing the side-chain protected compound from the previous step, e.g. 2-( {[(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyπolidinyl] carbo- nyl}amino)ethyl acetate (450mg, 10.6mmol) in THF (10ml). An aqueous solution (10ml) of sodium hydroxide (75mg, 19mmol) with methanol (5ml) was added and the reaction stiπed at room temperature for three hours. The solvent was removed in vacuo and the crude purified by column chromatography using THF (100%) to give the expected final product, e.g. (2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2- pyπolidinecarboxamide (300mg, 75%) as a white solid.
IH ΝMR (400 MHz, CDC13); 2.85-3.0 (m, IH), 3.3-3.6 (m, 3H), 3.7-3.8 (2H), 3.85-3.95 (m, 3H), 4.2=4.5 (m, 2H), 5.15-5.25 (m, IH), 7.2-7.9 (m, 9H). M+(APC ); 382.
Example 10: (2S.4EZ)-1-(T1 J,-biphenyl]-4-ylcarbonylVN-r(2RS)-2-hydroχy-2-phenethvn-4- (methoxyimmo -2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 9, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [l,l'-biphenyl]-4-carbonyl chloride, and 2-amino-l-phenylethyl acetate, the title compound was obtained after column chromatography as a mixture of Ε/Z-isomers as an off-white solid. The two isomers could be separated by another flash chromatographic purification step.
(2S,4E)-l-([l,r-biρhenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-
(methoxyimino)-2-pyπolidinecarboxamide: IH ΝMR (400 MHz, CDC13); 2.75-2.9 (m, IH), 3.1-3.25 (m, 2H), 3.35-3.6 (m, IH), 3.7-3.8 (m, IH), 3.75 (s, 3H), 4.1-4.3 (m, 2H), 4.8 ( , IH), 5.1 (dd, IH), 7.1-7.6 ( , 15H). M+(APCI ); 458.
(2S,4Z)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4- (methoxyimino)-2-pyπolidinecarboxamide: IH ΝMR (400 MHz, CDC13); 2.7-2.85 (m, IH), 3.05-3.25 (m, 2H), 3.35 (m, IH), 3.65-3.8 (m, IH), 3.8 (s, 3H), 4.15-4.25 (d, IH), 4.25-4.4 (m, IH), 4.75 (m, IH), 5.1 (dd, IH), 7.15-7.6 (m, 15H). M+(APC ); 458.
Example 11 : General protocol for the solution-phase synthesis of oximether pyrrolidine derivatives of general formula lb (Scheme 5); (3EZ,5S)-5-(lH-benzimidazol-2-ylVl-([l,r- biphenyl]-4-ylcarbonyl -3-pyπolidinone O-methyloxime
a) Protocol for the formation of the amide bond
A solution was prepared containing the central building block, e.g. (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid (Intermediate 7) (2.1g, δ.lmmol), an ortho-substituted aromatic amine or amine salt, e.g. 1,2-benzenediamine (0.88g, δ.lmmol) and DMAP (1.59g, 13.0mmol). in dry dichloromethane (30ml). This solution was cooled to 0°C and treated with ΕDC (1.56g, 8.2mmol) before warmmg to room temperature and stirring for 2 days. The solvent was removed in vacuo and the product purified by silica gel chromatography, eluting with a gradient of 30-80% ethyl acetate in hexane to give the desired anilide product, e.g. tert-butyl (2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4- (methoxyimino)-l-pyπolidinecarboxylate 2.8g, 97% as a colourless foam.
1Η ΝMR (360MHz, CDC13); 1.7, (m, 9H), 2.5-3.5 (br, 4H), 3.4 (m, IH), 4.0 (m, 3H), 4.2-4.4 (m, 2H), 4.9 (m, IH), 6.9-7.5 (m, 4H), 8.5 (br, IH).
b) Protocol for the formation of the fused heterocyclic ring
A solution of the anilide compound from the previous step, e.g. tert-butyl (2S,4EZ)-2-[(2- aminoanilmo)carbonyl]-4-(methoxyimino)-l-pyπolidinecarboxylate (0.8g, 2.3mmol) in dichloromethane (30ml) and acetic acid (3ml) was stiπed at room temperature for 3 days. Saturated aqueous sodium bicarbonate (7ml) was added to the reaction, the organic phase collected and dried over magnesium sulfate before filtering and removal of solvent in vacuo to give the desired product, e.g. tert-butyl (2S,4EZ)-2-(lH-benzimidazol-2-yl)-4-(methoxy- imino)-l-ρyπolidinecarboxylate (740mg, 97%) as an off-white foam.
1Η NMR (360MHz, CDC13); 1.5 (m, 9H), 3.1 (m, IH), 3.8 (m, 3H) 3.9-4.3 (m, 3H), 5.3 (m, IH), 7.1-7.6 (m, 4H), 10-10.5 (br, IH).
c) Protocol for the N-deprotection step
Hydrogen chloride gas was bubbled into a solution of the fused heterocyclic product from the previous step, e.g. tert-butyl (2S,4EZ)-2-(lH-benzimidazol-2-yl)-4-(methoxyimino)-l- pyπolidinecarboxylate (740mg, 2.2mmol) in dry DCM (20ml) for 30 min.. The solvent was removed in vacuo to give the desired product, e.g. (3EZ,5S)-5-(lH-benzimidazol-2-yl)-3- pyπolidinone O-methyloxime (0.58g, 99%), as a brown amorphous powder which was used without further purification.
d) Protocol for the N-capping step
A solution of the free NΗ product from the previous step, e.g. (3EZ,5S)-5-(lH-benzimida-zol- 2-yl)-3-pyπolidinone O-methyloxime (0.58g, 2.2mmol) in dry dichloromethane (25ml) was treated with an acid chloride, e.g. [l,l'-bip__enyl]-4-carbonyl chloride (0.48g, 2.2mmol) and triethylamine (0.9ml, 6.6mmol). The resultmg solution was then stiπed for 3h at room temp before removal of solvent in vacuo and the desired isomers were isolated by flash chromatography on silica gel, eluting with a gradient of ethyl acetate (10-80%) in hexane to give the two isomers (120mg of the less polar and 400mg of the more polar) of the desired product, e.g. (3E,5S)- and (3Z,5S)-5-(lH-benzimidazol-2-yl)-l-([l,l'-biphenyl]-4-ylcarbo- nyl)-3-pyπolidinone O-methyloxime, as off-white powders.
(3E,5S)-5-(lH-benzimidazol-2-yl)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-3-pyπolidinone O- methyloxime: 1Η NMR (360MΗz, CDC13); 3.2, (m, IH), 3.8 (s, 3H), 4.0 (m, IH), 4.3 (m, 2H), 6.0 (m, IH), 6.0 (m, IH), 7.2-7.7 (m, 13H), 10-11 (br, IH). M+(APCf); 411. (3Z,5S)-5-(lH-benzimidazol-2-yl)-l-([l,r-biphenyl]-4-ylcarbonyl)-3-pyπolidinone O- methyloxime: 1Η NMR (360MΗz, CDC13); 3.1, (m, IH), 3.8 (s, 3H), 3.9 (m, IH), 4.3 (m, 2H), 6.0 (m, IH), 6.0 (m, IH), 7.2-7.7 (m, 13H), 10-11 (br, IH). M+(APCI+); 411.
Example 12: f3EZ5S)-5-(lH-benzimidazol-2-vn-l-r(2'-methyiriJ'-biphenyll-4-yl -carbonyl]- 3 -pyrrolidinone O-methyloxime
Following the general method as outlined in Example 11, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l ,l'-biphenyl]-4- carboxylic acid, and 1,2-benzenediamine, the title compound was obtained in 91% purity by ΗPLC. MS(ΕSI+): m/z = 425.
Example 13 : (3EZ,5S)-5-(l -methyl- lH-benzimidazol-2-yl)- 1 -[(2'-methyl[ 1 , 1 '-biphenyl! -4- yl carbonyl]-3-pyrrolidinone O-methyloxime
Following the general method as outlined in Example 11, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, 2'-methyl[l,r-biphenyl]-4- carboxylic acid, and N^methyl-l^-benzenediamine, the title compoxmd was obtained in 83% purity by ΗPLC. MS(ΕSI+): m/z = 439.
Example 14: (3EZ.5S)-5-(7-hvdroxy-lH-benzimidazol-2-yl -l-r(2'-methviri J'-biρhenyll-4- yl carbonyl]-3-pyπolidinone O-methyloxime
Following the general method as outlined in Example 11, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l ,l'-biphenyl]-4- carboxylic acid, and 2,3-diaminophenol, the title compound was obtained in 91% purity by ΗPLC. MS(ΕSI+): m/z = 441.
Example 15 : (3EZ-5SV5-(3.4-dihvdro-2-quinazolinylV 1 -r(2'-methvir 1 , 1 '-biρhenyll-4- yDcarbonyl] -3 -pyπolidinone O-methyloxime
Following the general method as outlined in Example 11, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[ 1,1 '-biphenyl] -4- carboxylic acid, and 2-(aminomethyl)aniline, the title compound was obtained in 77% purity by HPLC. MS(ESI+): m/z = 439.
Example 16 : (3EZ.5SV 1 -(\ 1 , 1 '-biphenyl] -4-ylcarbonylV 5-(l -methyl- lH-benzimidazol-2-vn-3- pyπolidinone O-methyloxime
Following the general method as outlined in Example 11 , starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyrrolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and N^methyl-l^-benzenediamine, the title compound was obtained in 88% purity by ΗPLC. MS(ESI+): m/z = 425.
Example 17: General protocol for the solution-phase synthesis of oxime or hydrazone pyπolidine derivatives of general formula I (Scheme 6); (2S, 4EZ)-l-([l,l'-biphenyl]-4- ylcarbonyl)-4-(hvdroxyimino)-N-[(2i?S)-2-hydroxy-2-phenethyl]-2-pyπolidine-carboxamide.
a) Protocol for the hydrolysis of the oximether group.
The starting oximether compounds, e.g. (2S,4EZ)-l-([l,l*-biρhenyl]-4-ylcarbonyl)-N-[(2RS)- 2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide, were obtained following the general methods as outlined, e.g., in Example 2, 11 or 22. A solution containing the oximether compoxmd was prepared, e.g. (2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N- [(2RS)-2-hydroxy-2-phenethyl]-4-(methoxyimino)-2-pyπolidinecarbox-amide (64 mg, 0.14 mmol), paraformaldehyde powder (95%, 42 mg, 1.41 mmol) and Amberlyst® 15 (30 mg) in acetone containing 10% of water (2 L). The reaction was stiπed 4 h at 60°C. Insoluble materials were filtered off and washed with a small amount of acetone. The filtrate was concentrated and the residue was diluted with DCM (15 mL). The organic solution was washed with brine (10 mL), dried over Νa2SO , and concentrated. The desired ketocarbonyl product, e.g. (2S)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo- 2-pyπolidmecarboxamide (56 mg, 92%) was isolated as a yellow oil and used without further purification.
b) Protocol for the formation of oxime and/or hydrazone compounds A solution was made containing the keto-pyπolidine derivative from the previous step, e.g. (2S)- 1 -([ 1 , 1 '-biρhenyl]-4-ylcarbonyl)-N-[(2i-S)-2-hydroxy-2-phenethyl]-4-oxo-2-pyπoli- dinecarboxamide (46 mg, 0.11 mmol) and hydroxylamine hydrochloride (12 mg, 0.17 mmol) in chloroform (1 ml) containing triethylamine (29 mg, 0.29 mmol). The reaction mixture was then stiπed at ambient temperature for one day, prior to removal of solvent. The resultant crude reaction mixture was purified by column chromatography using DCM MeOH (25:1) to collect the desired product, e.g. (2S, 4EZ)-l-([l, -biphenyl]-4-ylcarbonyl)-4-(hydroxy-imino)- N-[(2RS)-2-hydroxy-2-phenethyl]-2-pyπolidme-carboxamide as a mixture of two isomers as an off-white solid (46 mg, 96% yield).
1H ΝMR (300 MHz, CDC13); 2.6-3.3 (m, 4H), 4.0-4.7 (m, 4H), 4.9 ( , IH), 5.5 (m, IH), 7.1- 7.5 ( , 8H), 7.6-7.8 (m, 5H), 8.1 (m, IH), 10.9 (m, IH). M+(APCΫ); 444.
Example 18: (2S.4EZ)-1-(F1 J'-biphenyl]-4-ylcarbonyl -4-(dimethylhvdrazonoVN-r(2RS)-2- hvdroxy-2-phenylethyri-2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 17, starting from (2S)-1-([1,1'~ biρhenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-ρhenylethyl]-4-oxo-2-pyπolidinecarbox- amide and N^N-dimethylhydrazine, the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (30:1) to collect the desired product, e.g. (2S,4EZ)-1 -([1,1 '-biphenyl]-4-ylcarbonyl)-4-(dimethylhydrazono)-N-[(2RS)-2-hydroxy-2- phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers as a light yellow oil in 56% yield (90.2 % purity by HPLC).
1H ΝMR (300 MHz, CDC13); 2.35-2.55 (br s, 3H), 2.40-2.60 (m, IH), 2.75-3.55 (m, 5H), 3.55-3.82 (m, IH), 3.90-4.4 (m, 2H), 4.83 (m, IH), 4.93-5.35 ( , IH), 7.18-7.49 (m, 9H), 7.49-7.68 (m, 5H). M+(APCI+); 471. M'(APCT); 469.
Example 19: (2S.4EZ)-l-(ri.r-biphenyl]-4-ylcarbonyl -N-r(2RS)-2-hydroxy-2-phenylethyl]-4- (methylhydrazono -2-pyπolidinecarboxamide Following the general method as outlined in Example 17, starting from (2S)-1-([1,1'- biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyπolidinecarbox- amide and N-methylhydrazine, the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (30:1) to collect the desired product, e.g. (2S,4EZ)-1- ([l,l'-biρhenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methylhydrazono)-2- pyπolidinecarboxamide as amixture of two isomers as a colorless solid in 57% yield (95.2 % purity by HPLC).
1H ΝMR (300 MHz, CDC13); 2.45-2.70 (m, IH), 2.85 (br s, 3H, ΝΝHCH5), 2.85-3.5 (m, 2Η), 3.51-4.4 (m, 4H), 4.84 (br s, IH, NNHMe), 4.95-5.35 (m, 1Η), 7.18-7.67 (m, 14Η). M+(APC ); 457. M"(APCT); 455.
Example 20 : (2SAEZ)- 1 -(r 1.1 '-biphenvn-4-ylcarbonyn-4-hvdrazono-N-[(2RS)-2-hvdroχy-2- phenylethyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 17, starting from (2S)-1-([1,1'- biphenyl]-4-ylcarbonyl)-N-[(2J-S)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyπolidinecarbox- amide and hydrazine hydrate (4% in EtOH), the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (30:1) to collect the desired product, e.g. (2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2i?S)-2-hydroxy-2-phenylethyl]-2- pyrrolidinecarboxamide as a mixture of two isomers as a colorless solid in 63% yield (95.3 % purity by HPLC).
1H ΝMR (300 MHz, DMSO-tf6, 80°C); 2.55 (dd, J= 9.8; 17.6 Hz, IH), 2.73 (dd, J= 9.8; 18.2 Hz, IH), 3.28 ( , 2H), 4.12 (m, 2H), 4.61 (m, IH), 4.85 (m, IH), 5.15 (m, IH), 5.70 (br s, 2H, ΝH Ν=C), 7.17-7.43 ( , 6Η), 7.44-7.60 (m, 4H), 7.66-7.77 (m, 5H). M+(APC ); 443. M" (APCT); 441.
Example 21 : (2S.4EZ)-4-(acetylhvdrazonoVl-([l J'-biphenyl1-4-ylcarbonyl -N-r(2J?S)-2- hydroxy-2-phenylethyl]-2-pyπolidinecarboxamide A hydrazono pyπolidine derivative obtained by the general method outlined in Example 17, e.g. (2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2- phenylethyl]-2-pyπolidinecarboxamide (51 mg, 0.11 mmol) was dissolved in pyridine (1 mL). Acetic anhydride (3 eq, 32 μl, 0.35 mmol) was added, and the mixture was stiπed overnight. The solvent was evaporated and the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (20:1) to collect the desired product, e.g. (2S,4EZ)-4- (acetylhydrazono)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2- pyrrolidinecarboxamide as a mixture of two isomers as a colorless solid in 73% yield (98.4 % purity by HPLC).
1H ΝMR (300 MHz, DMSO-</6, 80°C); 1.99 (br s, 3H, CH3COΝ), 2.7-3.4 (m, 5Η), 4.26 (m, 2H), 4.63 (m, IH), 4.89 (m, IH), 5.15 (m, IH), 7.18-7.44 (m, 6H), 7.45-7.62 (m, 4H), 7.66- 7.85 (m, 5H), 9.97 (br s, IH, MeCONHN, major isomer), 10.04 (br s, 1Η, MeCONHN, minor isomer). M+(ΕSl"); 485. M"(EST); 483.
Example 22: General protocol for the solid-phase synthesis of pyπolidine derivatives of general formula I.
a) Loading step
Kaiser oxime resin (16.5g, loading 1.57mmol/g) was added to a solution of the relevant pyπolidine carboxylic acid building block (51.8mmol) and diisopropylcarbodiimide (8.1ml, 51.8mmol) in dry dichloromethane (150ml). The resulting suspension was shaken overnight before filtering at the pump and washing sequentially with DMF, DCM and finally diethyl ether before drying at room temperature in vacuo.
b) N-deprotection step
The resin obtained in the loading step was shaken with a 20% solution of trifluoroacetic acid in dichloromethane (200ml) for 30 minutes prior to filtering at the pump and washing sequentially with aliquots of DMF, DCM and finally diethyl ether before drying at room temperature in vacuo. c) N-capping step
The resin from the previous step was transfeπed into a 96-well filter-plate (approx. 50mg of dry resin/well) and each well treated with an N-reactive derivatising agent, e.g. with either of the following solutions:
a) an acid chloride (0.165mmol) and diisopropylethylamme (0.165mmol) in dry dichloromethane (1ml), overnight
b) an acid (0.165mmol) and DIC (0.165mmol) in, depending on the solubility of the carboxylic acid, dry dichloromethane or ΝMP (1 ml) overnight.
c) an isocyanate (0.165mmol) in dry THF (1ml), overnight
d) a sulfonyl chloride (0.165mmol) and diisopropylethylamme (0.165mmol) in ΝMP (1ml), overnight.
e) a benzyl (alkyl) bromide (0.165mmol) and diisopropylethylamme (0.165mmol) in ΝMP (lml), overnight.
f) a vinyl ketone (0.165mmol) in THF, overnight
g) diketene (0.165mmol) in THF, overnight
The plate was then sealed and shaken overnight at ambient temperature. The resins were then filtered, washing the resin sequentially with aliquots of DMF, DCM and finally diethyl ether before drying at room temperature in vacuo.
d) Cleavage step A solution of amine (0.05mmol) in 2% AcOH in dichloromethane (lml) was added to each well containing the resin from the previous step. The plate was then sealed and shaken for two days at ambient temperature. The wells were then filtered into a collection plate and the solvent removed in a vacuum centrifuge to yield 2-3 mg of the coπesponding products, generally obtained as oils. The products were characterised by LC (205nm) and mass spec- trometry (ES+). All of the following examples were identified based on the observation of the coπect molecular ion in the mass spectrum, and were shown to be at least 40% pure (usually 60-95% pure) by LC.
Example 23 : (2S,4EZ -N2-(2-hydroχyethyl -4-(methoxyimino -N1 -pentyl- 1 ,2-pyπolidine- dicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 1-isocyanatoρentane, and 2- aminoethanol the title compound was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 315.2.
Example 24 (2S.4E'Z)-4-benzylidene-l-(ri. -biρhenyn-4-ylcarbonyl)-N-r2-(diethylaminoV ethyl] -2-p vHolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzy- lidene-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, [l,l'-biphenyl]-4-carbonyl chloride, and Νl,Νl-diethyl-l,2-ethanediamine the title compound was obtained in 90% purity by LC/MS. MS(ESI+): m z = 482.4.
Example 25: (2S.4EZ)-4-f(allyloxy)imino]-l-(4-cvanobenzoylVN-r2-(lH-ρvπol-l-yl)phenvn- 2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 2-(lΗ-pyπol- 1 -yl)phenylamine the title compound was obtained in 51 % purity by LC/MS. MS(ΕSI+): m/z = 454.4.
Example 26: (2S EZ)-4-{r(3.4-dichlorobenzynoχy1imino -N-(2-furylmethyl -l- (2-oxo-6- ρentyl-2H-pyran-3-yl)carbonyl]-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidmecarboxylic acid, 2-oxo-6- pentyl-2H-pyran-3-carbonyl chloride, and 2-furylmethylamine the title compound was obtained in 92% purity by LC/MS. MS(ESI+): m/z = 574.4.
Example 27: (2S,4EZ)-4-(methoxyimino -N1-(3-methoxyphenyl -N2-(2-thienylmethyl -l-2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4E2)-l-(/ert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 1 -isocyanato-3 -methoxy- benzene, and 2-thienylmethylamine the title compound was obtained in 79% purity by LC/MS. MS(ΕSI+): m/z = 403.2.
Example 28: (2S.4EZ)-2-{|"4-(l,3-benzodioxol-5-ylmethylVl-piρerazinyl]carbonyl>-4- (methoxyimino)-N-pentyl- 1 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 1-isocyanatopentane, and 1- (l,3-benzodioxol-5-ylmethyl)ρiperazine the title compound was obtained in 72% purity by LC/MS. MS(ΕSI+): m/z = 474.4.
Example 29: (2S.4EZ)-4-r(benzyloxy)imino1-l-(4-cvanobenzoyl)-N-(2-fύrylmethyl')-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 2-furylmethylamine the title compound was obtained in 49% purity by LC/MS. MS(ΕSI+): m/z = 443.4.
Example 30: (2S,4EZ -4- (benzyloxy imino]-N-[2-(diethylamino ethyl]-l-(4-ρhenoχyben- zoyl)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and Nl,Nl-di ethyl- 1,2-ethanediamine the title compoxmd was obtained in 86% purity by LC/MS. MS(ESI+): m/z = 529.6.
Example 31 : 4- ((2S,4EZ -4-f(benzyloxy)immo]-2- {[4-(3,4-dichlorophenyl)-l -piperazinyl]- carbonyl I pyπolidinyl)carbonyl]benzonitrile
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-ρyπolidmecarboxylic acid, 4-cyanobenzoyl chloride, and l-(3,4-dichlorophenyl)piperazine the title compound was obtained in 43% purity by LC/MS. MS(ΕSI+): m/z = 576.6.
Example 32: (2S.4EZ)-4-(methoxyimino)-N1-pentyl-N2-r2-(lH-ρyrrol-l-ynphenyl]- 2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 1-isocyanatopentane, and 2- (lΗ-pyrrol-l-yl)phenylamine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z = 412.2.
Example 33: (2SAEZ)-\ -acryloyl-4- {r(3,4-dichlorobenzyl oxy]immo -N-(2-furylmethyl -2- pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, acryloyl chloride, and 2-furylmethylamine the title compound was obtained in 74% purity by LC/MS. MS(ΕSI+): m/z = 436.8.
Example 34: (2S.4EZ)-4-(tert-butoχyimino -N2-cvcloρroρyl-N1-(3-5-dichlorophenyl -l 2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(tert-butoxyimino)-2-pyπolidmecarboxylic acid, 1 ,3-dichloro-5-iso- cyanatobenzene, and cyclopropylamine the title compoxmd was obtained in 48% purity by LC/MS. MS(ESI+): m/z = 427.6.
Example 35: (2S,4EZ)-4-[(allyloxy imino1-N- 2-(diethylamino ethyl1-l-r(2-oxo-6-ρentyl-2H- pyran-3 - vDcarbonyl] -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-
[(allyloxy)-imino]-l -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η- pyran-3-carbonyl chloride, and Νl,Νl-diethyl-l,2-ethanediamine the title compoxmd was obtained in 93% purity by LC/MS. MS(ΕSI+): m/z = 475.4.
Example 36: (2S.4EZ)-iV2-r(2i?S)-2-hydroxy-2-phenethyl1-4-(methoχyiminoVN1 -(3- methylphenyl)- 1 ,2-p vπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1 -isocyanato-3- methylbenzene, and (lRS)-2-amino-l-phenylethanol the title compound was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 411.2.
Example 37: (2SAEZ)-1 - (benzoylamino carbonyl]-N-benzyl-4-[(benzyloxy)imino]-N- methyl-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, benzoyl isocyanate, and Ν- benzyl-Ν-methylamine the title compound was obtained in 40% purity by LC/MS. MS(ΕSI+): m z = 485.4.
Example 38: (2S.4EZ)-l-(4-cyanobenzoylVN-(9-ethyl-9H-carbazol-3-ylV4-(methoχyimino - 2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 72% purity by LC MS. MS(ESI+): m/z = 480.4.
Example 39: (2S.4EZ)-4-(methoχyimino -N1 -(3-methylphenvn-N2-(2-thienylmethyl -l ,2- pyπolidmedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 1 -isocyanato-3-methyl- benzene, and 2-thienylmethylamine the title compound was obtained in 98% purity by LC/MS. MS(ΕSI+): m/z = 387.2.
Example 40: (2S.4EZ)-4-(tert-butoxyimino -N-(2-methoxyethvD-l -f(2-oxo-6-pentyl-2H- pyran-3-yl)carbonyl -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(tert-butoxyimino)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η- pyran-3 -carbonyl chloride, and 2-methoxyethylamine the title compound was obtained in 75% purity by LC/MS. MS(ΕSI+): m/z = 450.2.
Example 41: (3EZ,5S)-5-{[4-(l,3-benzodioxol-5-ylmethyl)-l-piperazinyl]carbonyl>-l- benzo yl-3 -pyπolidinone O-(3.4-dichloroben vDoxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, benzoyl chloride, and l-(l,3-benzodioxol-5-ylmethyl)piperazine the title compound was obtained in 71% purity by LC/MS. MS(ΕSI+): m/z = 609.8.
Example 42: tert-butyl 3- ({(2S.4EZ)-4-(ethoxyimino -l-r(2-oxo-6-pentyl-2H-pyran-3- yl carbonyl]pyrrolidinyllcarbonyl amino1-l-azetidinecarboxylate
Following the general method as outlined in Example 22, starting from (2S,4EZ -\-(tert- butoxycarbonyl)-4-(ethoxyimmo)-2-pyπolidmecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carbonyl chloride, and tert-butyl 3-amino-l-azetidinecarboxylate the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z = 519.6.
Example 43: (2S-4EZ)-4-{J(4-methoxybenzyl oxy]imino>-N-(3-methylρhenyl -2-(4-morpho- linylcarbonylV 1 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4- { [(4-methoxybenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, 1 - isocyanato-3-methylbenzene, and morpholme the title compoxmd was obtained in 41% purity by LC/MS. MS(ΕSI+): m/z = 467.4.
Example 44: (2S,4EZ)-N2-cyclopropyl-4-- [(4-methoχybenzyl)oxy]imino)-N1-pentyl-l,2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, 1 - isocyanatopentane, and cyclopropylamine the title compound was obtained in 75% purity by LC/MS. MS(ΕSI+): m z = 417.2.
Example 45: (3EZ.5S)-5-ir4-(3.4-dichlorophenylVl-ρiρerazinyl]carbonyll-l-r(2-oxo-6- pentyl-2H-pyran-3-yl)carbonyl]-3-pyπolidinone O-benzyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino] - 1 -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3 - carbonyl chloride, and l-(3,4-dichlorophenyl)piperazine the title compoxmd was obtained in 47% purity by LC/MS. MS(ΕSI+): m/z = 639.8.
Example 46: (2S.4EZ)-4-(tert-butoχyimino -N-r2-(lH-pyrrol-l-yl phenyl]-2-pyrrolidine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(tert-butoxyimino)-2-pyπolidmecarboxylic acid, and 2-(lΗ-pyπol-l- yl)phenylamine the title compoxmd was obtained in 83% purity by LC/MS. MS(ESI+): m/z = 341.2.
Example 47: l-({(2S,4EZ)-4-(chloromethylene)-l-[(4-chlorophenoxy)acetyl]pyrrolidinyl>- carbonyl -4-(3-4-dichlorophenyl piρerazine
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, (4-chlorophenoxy)acetyl chloride, and l-(3,4-dichlorophenyl)piperazine the title compound was obtained in 64% purity by LC/MS. MS(ΕSI+): m/z = 543.6.
Example 48: (2S,4EZ)-4- (benzyloxy imino]-N-(4.6-dimethoxy-2-pyrimidinyl)-l-[(2-oxo-6- pentyl-2H-ρyran-3-yl)carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]- 1 -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carbonyl chloride, and 4,6-dimethoxy-2-pyrimidinamine the title compound was obtained in 62% purity by LC/MS. MS(ΕSI+): m/z = 564.6.
Example 49: (2S,4EZ)-4--f[(3,4-dichlorobenzyl)oxy]imino>-l-[4-(dimethylamino)butanoyl]- N-( 1 -naphthylmethyl)-2-p yπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(3,4-dichlorobenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, 4- (dimethylamino)butanoyl chloride, and 1-naphthylmethylamine the title compound was obtained in 62% purity by LC/MS. MS(ΕSI+): m/z = 555.6.
Example 50: (2S)-N2-(2.1.3-benzothiadiazol-4-yl)-N1-(3.5-dichloroρhenyl)-4-oxo-l .2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxy- carbonyl)-4-oxoproline, l,3-dichloro-5-isocyanatobenzene, and 2,l,3-benzothiadiazol-4-amine the title compound was obtained in 47% purity by LC MS. MS(ESI+): m/z = 450.6. Exa ple 51 : (2S,4EZ)-N-benzyl-4-(chloromethylene)-N-methyl-l -(4-phenoxybenzoyl -2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and Ν-benzyl-Ν-methylamine the title compound was obtained in 61% purity by LC/MS. MS(ΕSI+): m z = 461.4.
Example 52: (2S.4EZ)-N2-(9-ethyl-9H-carbazol-3-yl)-4-{ (4-methoχybenzyl')oxy]imino>-N1- (3 -methylphenyl - 1 ,2-p yπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- { [(4-methoxybenzyl)oxy] imino } -2-pyπolidinecarboxylic acid, 1 -isocya-nato- 3-methylbenzene, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 72% purity by LC/MS. MS(ΕSI+): m z = 590.8.
Example 53 : (2S)-N-(tert-butyl)-4-methylene- 1 -r(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2- pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxy- carbonyl)-4-methyleneproline, 2-oxo-6-pentyl-2Η-pyran-3-carbonyl chloride, and tert- butylamine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z = 375.4.
Example 54: (2S,4EZ)-4-benzylidene-l-[4-(dimethylamino butanoyl]-N-(6-quinolinyl)-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzyli- dene-1 -(tert-butoxycarbonyl)-2-pyπolidmecarboxylic acid, 4-(dimethylamino)butanoyl chloride, and 6-quinolinamine the title compoxmd was obtained in 71% purity by LC/MS. MS(ESI+): m/z = 443.6. Examρle 55: (2S)-l-[4-(dimethylamino butanoyl]-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene- 2-pyrrolidmecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, 4-(dimethylamino)butanoyl chloride, and 9-ethyl-9Η-carbazol-3- amine the title compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z = 433.6.
Example 56 : (2SAEZ)-N-( 1 ,3-benzodioxol-5 -ylmethyl)-4- (benzylox y)imino] - 1 -(4-c yano- benzoyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-ρyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 1 ,3-benzodioxol-5-ylmethylamine the title compoxmd was obtained in 51 % purity by LC/MS. MS(ΕSI+): m/z = 497.6.
Example 57 : (2S)- 1 -( ( 1 -[4-(dimethylamino butanoyl]-4-methylene-2-ρvπolidinyl> carbonyl)- 3-azetidinol
Following the general method as outlined in Example 22, starting from l-(tert-butoxy- carbonyl)-4-methyleneproline, 4-(dimethylamino)butanoyl chloride, and 3-azetidinol the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z = 296.4.
Example 58 : (2SAEZ)- 1 -(T 1.1 '-biphenyl .^ylcaibαnyl. -4- If (3.4-dichlorobenzyl)ox ylimino) - N- 2-(lH-pyπol-l-yDphenyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4- { [(3 ,4-dichlorobenzyl)oxy] imino } -2-pyπolidinecarboxylic acid, [1,1'- biphenyl]-4-carbonyl chloride, and 2-(lΗ-pyπol-l-yl)phenylamine the title compoxmd was obtained in 54% purity by LC/MS. MS(ΕSI+): m/z = 623.6.
Example 59: (2S,4EZ)-4-benzylidene-l-[(4-chlorophenoxy acetyl]-N-(3,4-dimethoxy-benzyl)- 2-pyrrolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzyli- dene-l-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, (4-chlorophenoxy)acetyl chlo-ride, and 3,4-dimethoxybenzylamine the title compoxmd was obtained in 49% purity by LC/MS. MS(ΕSI+): m/z = 521.6.
Example 60: (2S,4EZ -4-{r(3.4-dichlorober-Zyl oχy]imino>-l-(diphenylacetylVN-(2-thienyl- methyl -2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(/ert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, diphen- ylacetyl chloride, and 2-thienylmethylamine the title compound was obtained in 51% purity by LC/MS. MS(ΕSI+): m/z = 592.6.
Example 61 : (2S.4EZ)-N-(3,4-dimethoxybenzyl -l-(diphenylacetyl -4-(methoxyimino)-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 3 ,4-dimethoxybenzylamine the title compound was obtained in 74% purity by LC/MS . MS(ΕSI+): m/z = 502.6.
Example 62: (2S.4EZ)-N1-(3.5-dichlorophenyl -4-(ethoxyimmo)-N2-r2-(lH-pyrrol-l -vDphen- yl]- 1 ,2-pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, l,3-dichloro-5-isocyanato- benzene, and 2-(lΗ-pyπol-l-yl)phenylamine the title compoxmd was obtained in 54% purity by LC/MS. MS(ΕSI+): m/z = 500.6.
Example 63: (2S.4EZ)-N2-(1.3-benzodioxol-5-ylmethyl -4-{[(4-methoxybenzyl -oxy]imino>- N1 -pentyl- 1.2-pyπolidinedicarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-ρyπolidinecarboxylic acid, 1-isocyanatopentane, and l,3-benzodioxol-5-ylmethylamine the title compound was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 511.4.
Example 64: (2S,4EZ -N-benzyl-4- (benzyloxy imino1-l-(diphenylacetyl -N-methyl-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and Ν-benzyl-Ν-methylamine the title compoxmd was obtained in 42% purity by LC/MS. MS(ΕSI+): m/z = 532.4.
Example 65 : (2SAEZ)-N-(2, 1.3-benzothiadiazol-4-ylV 1 -(\ 1.1 '-biphenyl]-4-ylcarbonylV4- (methoxyimino)-2-ρyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1' -biphenyl] -4-carbonyl chloride, and 2,1 ,3-benzothiadiazol-4-amine the title compoxmd was obtained in 66% purity by LC/MS. MS(ΕSI+): m/z = 472.4.
Example 66: (2SAEZ)- 1 -( 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-qumolinyl)-2- pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxy imino)-2-pyπolidinecarboxylic acid, [1,1' -biphenyl] -4-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 79% purity by LC/MS. MS(ΕSI+): m/z = 465.4.
Example 67: (2S,4EZ)-l-acetoacetyl-N-benzyl-4-(methoxyimino -2-pyπolidinecarbox-amide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimmo)-2-pyrrolidinecarboxylic acid, 2,4-oxetanedione, and benzylamine the title compound was obtained in 45% purity by LC/MS. MS(ESI+): m/z = 332.2.
Example 68 : (2SAEZ)- 1 -(\ 1 , 1 '-biphenvn-4-ylcarbonyl -4-(chloromethylene)-N-(2-ftιryl- methyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)~l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, [1 ,1 ' -biphenyl] -4-carbo-nyl chloride, and 2-furylmethylamine the title compound was obtained in 70% purity by LC/MS. MS(ΕSI+): m/z = 421.4.
Example 69: (2S.4EZ)-l-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl oxy]immo>-N- [(2RS)-2-hydroxy-2-phenethyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, (4-chloro- phenoxy)acetyl chloride, and (lRS)-2-amino-l-phenylethanol the title compound was obtained in 62% purity by LC/MS. MS(ESI+): m/z = 590.8.
Example 70: (2S.4EZ)-N-allyl-l-(|"ia'-biρhenyl]-4-ylcarbonyl -4-(methoxyimino)-2-pyπo- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl]-4-carbonyl chloride, and allylamine the title compound was obtained in 87% purity by LC/MS. MS(ΕSI+): m/z = 378.2.
Example 71 : (2SAEZ)- 1 -0T , 1 '-biphenyl]-4-ylcarbonyl -4-(methox vimino)-N-(2-thien yl- methyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl]-4-carbonyl chloride, and 2-thienylmethylamine the title compound was obtained in 78% purity by LC/MS. MS(ESI+): m/z = 434.4.
Example 72: (2S,4EZ)-4-(cvanomethylene -N-(2-furylmethylVl-r(2-oxo-6-pentyl-2H-pyran- 3 -vDcarbonyl] -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carbonyl chloride, and 2-f rylmethylamine the title compound was obtained in 34% purity by LC/MS. MS(ΕSI+): m/z = 424.4.
Example 73 : (2SAEZ)- 1 -([ 1.1 '-biρhenyl]-4-ylcarbonylVN-(2-furylmethyl -4-(methoχy-imino)- 2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [l,F-biphenyl]-4-carbonyl chloride, and 2-furylmethylamine the title compound was obtained in 75% purity by LC/MS. MS(ΕSI+): m/z = 418.4.
Example 74 : (2S.4EZ)- 1 -acetyl-N-cyclopropyl-4- { [(3,4-dichlorobenzyl oxy]imino -2-pyπo- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(3 ,4-dichlorobenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, acetyl chloride, and cyclopropylamine the title compound was obtained in 52% purity by LC/MS. MS(ΕSI+): m/z = 384.4.
Example 75 (2S.4EZ)-N-(2-furylmethylV4-(methoxyimino - 1 -r(2-oxo-6-pentyl-2H-pyran-3- yl)carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3- carbonyl chloride, and 2-furylmethylamine the title compound was obtained in 62% purity by LC/MS. MS(ESI+): m/z = 430.4.
Example 76: (2S_4EZ)-N-benzyl-l-( l '-biphenyl]-4-ylcarbonyl -4-(methoxyimino')-N- methyl-2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl] -4-carbonyl chloride, and Ν-benzyl-Ν-methylamine the title compoxmd was obtained in 67% purity by LC/MS. MS(ΕSI+): m/z = 442.4.
Example 77: (2S,4EZ)-l-(diphenylacetyl -4-(ethoxyimino)-N-(2-thienylmethyl -2-pyπolidine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-buto- xycarbonyl)-4-(ethoxyimmo)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 2- thienylmethylamine the title compoxmd was obtained in 74% purity by LC/MS. MS(ΕSI+): m/z = 462.4.
Example 78: (2S,4EZ -N-(2,l,3-benzothiadiazol-4-yl -4-(cyanomethylene -l-(diphenylacetyl)- 2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(ter/-but- oxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 2,l,3-benzothiadiazol-4-amine the title compoxmd was obtained in 42% purity by LC/MS. MS(ΕSI+): m/z = 480.4.
Example 79 : (2S)- 1 -(diphenylacetyl -N-( 1 -naphthylmethyl)-4-oxo-2-p yrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-oxoproline, diphenylacetyl chloride, and 1-naphthylmethylamine the title compoxmd was obtained in 60% purity by LC MS. MS(ESI+): m z = 463.4. Example 80: (3EZ.5S -5-(lH-benzimidazol-2-yl)-l-(diphenylacetyl -3-pyπolidinone O- methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 1 ,2-benzenediamine the title compound was obtained in 72% purity by LC/MS. MS(ΕSI+): m/z = 425.4.
Example 81: (2S)-2-[l-([l. -biphenyl]-4-ylcarbonyl -4-methylene-2-pyπolidinyll-lH-benz- imidazole
Following the general method as outlined in Example 22, starting from l-(tert-butoxy- carbonyl)-4-methyleneproline, [l,l'-biphenyl]-4-carbonyl chloride, and 1,2-benzenedi-amine the title compound was obtained in 73% purity by LC MS. MS(ESI+): m/z = 380.4.
Example 82: (2S.4EZ)-l-(riJ'-biρhenyl]-4-ylcarbonyl -4-(chloromethyleneVN-(2-methoχy- ethyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, [1,1 ' -biphenyl] -4- carbonyl chloride, and 2-methoxyethylamine the title compoxmd was obtained in 55% purity by LC/MS. MS(ΕSI+): m/z = 399.6.
Example 83: (3EZ-5S)-5-(lH-benzimidazol-2-yl -l-(diphenylacetyl)-3-pyπolidinone O- allyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-
[(allyloxy)-imino]- 1 -(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 1,2-benzenediamine the title compound was obtained in 63% purity by LC/MS. MS(ΕSI+): m z = 451.4.
Example 84: (2SAEZ)- 1 -(IT .1 '-biρhenvn-4-ylcarbonvn-N-r2-(diethylamino)ethyl]-4- (methoxyiminoV2-pyπolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl]-4-carbonyl chloride, andNl,Nl-diethyl-l,2-ethanediamine the title compound was obtained in 90% purity by LC/MS. MS(ΕSI+): m/z = 437.4.
Example 85: (2S.4EZ)-l-(diphenylacetylV4-{r(4-methoχybenzyl oxy]iminol-N-(2-thienyl- methyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino) -2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 2-thienylmethylamine the title compoxmd was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 554.4.
Example 86: (2S.4EZ)-l-([l.r-biphenyl]-4-ylcarbonyl -N-(3,4-dimethoxybenzyl -4-(methoxy- immo -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)~2-pyπolidinecarboxylic cid, [l,l'-biphenyl]-4-carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 58% purity by LC/MS. MS(ΕSI+): m/z = 488.4.
Example 87: (2S,4EZ)-l-acetoacetyl-4-(methoxyimino -N-(l-naphthylmethyl -2-pyrroli-dine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2,4-oxetanedione, and 1- naphthylmethylamine the title compound was obtained in 40% purity by LC/MS. MS(ΕSI+): m z = 382.2.
Example 88: (2S.4EZ)-N-allyl-4-{r(3.4-dichlorobenzyl oxy1imino)-l-(diphenylacetyl)-2- pyrrolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and allylamine the title compound was obtained in 54% purity by LC/MS. MS(ΕSI+): m/z = 536.6.
Example 89: (2S,4EZ)-4-{f(3-4-dichlorobenzyl oxy]imino)-N1-ρentyl-N2-(6-quinolinyl)-1.2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(3,4-dichlorobenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, 1 -isocya- natopentane, and 6-quinolinamine the title compound was obtained in 54% purity by LC/MS. MS(ΕSI+): m/z = 542.6.
Example 90: (2S,4EZ)-4-(chloromethylene)- 1 -(diphenylacetyl)-N-r(2RS -2-hydroxy-2- phenethyl] -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and (lRS)-2-amino-l-phenylethanol the title compoxmd was obtained in 87% purity by LC/MS. MS(ΕSI+): m/z = 475.4.
Example 91: (2S)-l-([lJ'-biphenyl1-4-ylcarbonyl -N-[(2RS)-2-hvdroχy-2-phenethvn-4- methylene-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, [1,1 '-biphenyl] -4-carbonyl chloride, and 2-amino-l-phenyl- ethanol the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z = 427.4.
Example 92 : (2SAEZ)- 1 -0" 1 , 1 '-biphenyl]-4-ylcarbonyl -4-(chloromethylene -N-(6-quinolmyl - 2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, [1,1' -biphenyl] -4-carbo-nyl chloride, and 6-quinolinamine the title compoxmd was obtained in 73% purity by LC/MS. MS(ESI+): m/z = 468.4.
Example 93 : (2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-l -(diphenylacetyl)-2-pyπo- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzyli- dene-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and Nl,Nl-diethyl-l,2-ethanediamine the title compoxmd was obtained in 71% purity by LC/MS. MS(ΕSI+): m/z = 496.4.
Example 94 : (2SAEZ)- 1 -acetoacet yl-4-(methoxyimino)-N-(2-thienylmethyl)-2-pynoli- dinecar-boxamide
Following the general method as outlined in Example 22, starting from (2S,4E2)-l-(/ert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2,4-oxetanedione, and 2- thienylmethylamine the title compoxmd was obtained in 42% purity by LC/MS. MS(ΕSI+): m/z = 338.2.
Example 95: (2S,4EZ)-l-acetyl-4-{r(3.4-dichlorobenzynoχy]imino)-N-(2-hydroxy-2-phenyl- ethyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(3 ,4-dichlorobe_ιzyl)oxy]imino} -2-pyπolidinecarboxylic acid, acetyl chloride, and (li_S)-2-amino-l-phenylethanol the title compoxmd was obtained in 48% purity by LC/MS. MS(ΕSI+): m/z = 464.6.
Example 96: (2S.4EZ)-4-{r(3-4-dichlorobenzyl oχy]imino>-N1-(3,5-dichlorophenylVN2-(6- quinolinyl)- 1 ,2-p yπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1,3- dichloro-5-isocyanatobenzene, and 6-quinolmamine the title compound was obtained in 66% purity by LC/MS. MS(ESI+): m/z = 617.2.
Example 97 : (2S,4EZ)-4-(methoxyimino)-N-( 1 -naphthylmethylV 1 -(phenox yacetyl - 2-ρyrro- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and 1- naphthylmethylamine the title compoxmd was obtained in 99% purity by LC/MS. MS(ΕSI+): m/z = 432.2.
Example 98: (2S-4EZ)-4-(chloromethyleneVN-(3.4-dimethoxybenzyl -l-[(2-oxo-6-ρentyl-2H- pyran-3 -vDcarbonyl] -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-ρyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 51% purity by LC/MS. MS(ΕSI+): m/z = 503.4.
Example 99: (2S,4EZ)-l-(diphenylacetyl -4-(methoxyimipo -N-(2-thienylmethyl -2-pyπoli- dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecafboxylic acid, diphenylacetyl chloride, and 2- thienylmethylamine the title compound was obtained in 88% purity by LC/MS. MS(ΕSI+): m/z = 448.4.
Example 100: (2&4EZV N-benzyl-1 -(diphenylacetyl -4-(methoxyimino -2-pyπolidinecar- boxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and benzylamine the title compoxmd was obtained in 82% purity by LC/MS. MS(ESI+): m/z = 442.4.
Example 101: (2S.4EZ)-l-([ia'-biρhenyl]-4-ylcarbonyl -4-{r(3,4-dichlorobenzyl oχy]- immo)-N- 2-(diethylamino ethyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- { [(3 ,4-dichlorobenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, [1,1' -bi- phenyl]-4-carbonyl chloride, andΝl,Νl-diethyl-l,2-ethanediamine the title compound was obtained in 74% purity by LC/MS. MS(ΕSI+): m/z = 581.6.
Example 102: (2S.4EZ1-4- {[(3,4-dichlorobenzyl oxy1imino } - l-[4-(dimethylamino)buta-noyl]- N-(6-quinolinyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(3,4-dichlorobenzyl)oxy]imino} -2-pyrrolidinecarboxylic acid, 4-(dime- thylamino)butanoyl chloride, and 6-quinolinamine the title compound was obtained in 95% purity by LC/MS. MS(ESI+): m/z = 542.6.
Example 103: (2S.4EZ)-l-(r r-biphenyl1-4-ylcarbonyl)-N-(5-ethyl-1 .4-thiadiazol-2-yl -4- (methoxyimino)-2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and 5-ethyl-l,3,4-thiadiazol-2-amine the title compoxmd was obtained in 89% purity by LC/MS. MS(ΕSI+): m z = 450.2.
Example 104: (2S,4EZ)-N-benzyl-l-(|l '-biphenyl]-4-ylcarbonyl -4-(methoxyimino -2-pyπo- lidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl] -4-carbonyl chloride, and benzylamine the title compoxmd was obtained in 72% purity by LC/MS. MS(ESI+): m/z = 428.2.
Example 105: (2S.4EZ)-N-benzyl- 1 -(diphenylacetyl -4-(ethoxyimmo -2-pyπolidinecarbox- amide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and benzylamine the title compound was obtained in 53% purity by LC/MS. MS(ΕSI+): m/z = 456.4.
Example 106: (2S.4EZ)-N2-cycloρropyl-4-|[(3,4-dichlorobenzyl oxy]imino -N1-(3-methoxy- phenyl)- 1 ,2-pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, 1-isocya- nato-3-methoxybenzene, and cyclopropylamine the title compoxmd was obtained in 45% purity by LC/MS. MS(ΕSI+): m/z = 491.6.
Example 107: (2SAEZ)- 1 -(diphenylacetyl)-N-r(2RS)-2-hvdroxy-2-phenethyll-4- IIY4- methoxyben-zyl oxy]imino}-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and (lRS)-2-amino-l-phenylethanol the title compoxmd was obtained in 66% purity by LC/MS. MS(ΕSI+): m z = 578.4.
Example 108: (2S)-N-(2-furylmethyl)-4-methylene-l - (2-oxo-6-pentyl-2H-pyran-3- yl)carbonyl]-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(ter/-butoxycar- bonyl)-4-methyleneproline, 2-oxo-6-pentyl-2Η-pyran-3-carbonyl chloride, and 2-furyl- methylamine the title compoxmd was obtained in 43% purity by LC/MS. MS(ESI+): m/z = 399.2.
Example 109: (2S.4EZ)-N-(2,1.3-benzothiadiazol-4-vn-l-(diphenylacetyl)-4-(methoχy- imino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 2,l,3-benzothiadiazol-4-amine the title compoxmd was obtained in 69% purity by LC/MS. MS(ΕSI+): m/z = 486.4.
Example 110: (2S)- -(3.5-dichlorophenylVN2-(3.4-dimethoxybeι_zylV4-oxo-1.2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxy- carbonyl)-4-oxoproline, l,3-dichloro-5-isocyanatobenzene, and 3,4-dimethoxybenzylamine the title compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z = 466.6.
Example 111: (2S,4EZ)-N-benzyl-l-(diphenylacetyl)-4-(["(4-methoxybenzyl oxy]immo)-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and benzylamine the title compound was obtained in 60% purity by LC/MS. MS(ΕSI+): m/z = 548.4.
Example 112: (2S.4EZ)-l-benzoyl-4-{r(3,4-dichlorobenzyl oxyliminol-N-(6-quinolinyl)-2- pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(3,4-dichlorobenzyl)oxy]imino) -2-pyπolidinecarboxylic acid, benzoyl chloride, and 6-quinolinamine the title compoxmd was obtained in 67% purity by LC/MS. MS(ΕSI+): m/z = 533.6. Example 113: (2S.4EZ)-l-acetoacetyl-N-cvclopropyl-4-{[(3.4-dichlorobenzyl)oxy1imino>-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4- { [(3 ,4-dichlorobenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, 2,4- oxetanedione, and cyclopropylamine the title compoxmd was obtained in 76% purity by LC/MS. MS(ESI+): m/z = 426.6.
Example 114: (2SAEZ)-4- jJ(3-4-dichlorobenzyl oxy]iminol-N2-r(2RS)-2-hvdroxy-2- phenethv^-N^pentyl-l^-pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, 1-isocyanatopentane, and (lRS)-2-amino-l-phenylethanol the title compoxmd was obtained in 47% purity by LC/MS. MS(ΕSI+): m/z = 535.6.
Example 115: (2S,4EZ)-4-[(benzyloxy imino]-N-(l-naphthylmethyl -l-(phenoxyacetyl)-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 74% purity by LC/MS. MS(ΕSI+): m/z = 508.4.
Example 116: (2S)-l-([l.r-biphenyl]-4-ylcarbonyl -4-methylene-N-(6-quinolmyl -2-pyπoli- dinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxy- carbonyl)-4-methyleneproline, [1,1 '-biphenyl] -4-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 88% purity by LC/MS. MS(ESI+): m/z = 434.2.
Example 117: (2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl oxy]imino>-l-(diphenyl- acetyl -2-pyπolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycafbonyl)-4- {[(3,4-dichlorobenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and cyclopropylamme the title compound was obtained in 49% purity by LC/MS. MS(ΕSI+): m z = 536.6.
Example 118: (2S.4EZ)-l-(4-cyanobenzoyl)-4-(r(3.4-dichlorobenzvnoχy]imino>-N-(6- quinolinyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4- {[(3,4-dichlorobenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, 4- cyanobenzoyl chloride, and 6-quinolinamine the title compoxmd was obtained in 52% purity by LC/MS. MS(ESI+): m/z = 558.6.
Example 119: (2S -4-oxo-l-(phenoxyacetyl -N-[2-(lH-pyrrol-l-yl phenyl]-2-pyπolidine- carboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-oxoproline, phenoxyacetyl chloride, and 2-(lΗ-pyπol-l-yl)phenylamine the title compoxmd was obtained in 42% purity by LC/MS. MS(ESI+): m/z = 404.2.
Example 120: (2S,4EZ)-N-cvclopropyl-4- { [(3 ,4-dichlorobenzyl oxy]imino> - 1 -(methoxy- acetyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4- {[(3,4-dichlorobenzyl)oxy]imino} -2-ρyπolidinecarboxylic acid, methoxyacetyl chloride, and cyclopropylamme the title compound was obtained in 54% purity by LC/MS. MS(ESI+): m/z = 414.6.
Example 121: (2SAEZ)-N-(1.3-benzodioxol-5-ylmethyl)- 1 -(11 , 1 '-biphenyl1-4-ylcarbonyl)-4- (methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1' -biphenyl] -4-carbonyl chloride, and l,3-benzodioxol-5-ylmethylamine the title compound was obtained in 64% purity by LC/MS. MS(ESI+): m/z = 472.4.
Example 122: (3EZ.5S -5-[(4-acetyl-l-piperazmyl carbonyn-l-acryloyl-3-pyπolidinone O- (3 ,4-dichlorobenzyl)oxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- { [(3,4-dichlorobenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, acryloyl chloride, and 1-acetylpiperazine the title compound was obtained in 79% purity by LC MS. MS(ΕSI+): m/z = 467.6.
Example 123: (2S)-l-(ri.l'-biphenyll-4-ylcarbonyl)-N-(2-furylmethylV4-methylene-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, [l,l'-biphenyl]-4-carbonyI chloride, and 2-furylmethylamine the title compound was obtained in 94% purity by LC/MS. MS(ESI+): m/z = 387.2.
Example 124: (2S,4EZ)-4-(cvanomethylene)-N-(3,4-dimethoxybenzyl)-l-[(2-oxo-6-pentyl- 2H-pyran-3-yl)carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3 - carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 65% purity by LC/MS. MS(ESI+): m/z = 494.4.
Example 125: (2S,4EZ)-l-[(benzoylamino carbonyl]-4-(cvanomethylene -N-(9-ethyl-9H- carbazol-3-yl -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, benzoyl isocyanate, and 9- ethyl-9Η-carbazol-3 -amine the title compoxmd was obtained in 74% purity by LC/MS. MS(ΕSI+): m/z = 492.4. Example 126; (2SAEZ)- 1 -benzo yl-N- r2-(diethylamino ethyl] -4-(methoxyimino -2-pyrroli- dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, benzoyl chloride, and Νl,Νl-diethyl-l,2-ethanediamine the title compound was obtained in 80% purity by LC/MS. MS(ΕSI+): m/z = 361.2.
Example 127: (2S,4EZ)-N-r2-(diethylamino,)ethyl]-l-(diphenylacetvn-4-(ethoxyimmo -2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and Ν1,Ν1 -diethyl- 1,2-ethanediamine the title compound was obtained in 50% purity by LC/MS. MS(ΕSI+): m/z = 465.4.
Example 128: (2S.4EZ -N-(2J.3-benzothiadiazol-4-yl)-4-r(benzyloxy)imino1-l-(4-cvano- benzoyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 2,l,3-benzothiadiazol-4-amine the title compoxmd was obtained in 55% purity by LC/MS. MS(ΕSI+): m/z = 497.4.
Example 129: (2EZ)-f 5 -(lH-benzimidazol-2-yl -l-(r U '-biphenyl] -4-ylcarbonyl -3-pyrro- lidinylidene] ethanenitrile
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and 1,2-benzenediamine the title compoxmd was obtained in 70% purity by LC/MS. MS(ΕSI+): m/z = 405.2. Example 130: (2S.4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-l - (phenoxyacetyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and 9-ethyl-9Η-carbazol-3 -amine the title compound was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 488.6.
Example 131: (2S)-N2-(9-ethyl-9H-carbazol-3-yl -N1 -(3-methoχyphenvn-4-methylene-l,2- pyrrolidinedicarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, l-isocyanato-3-methoxybenzene, and 9-ethyl-9Η-carbazol-3- amine the title compoxmd was obtained in 47% purity by LC/MS. MS(ESI+): m/z = 469.4.
Example 132: (2SAEZ)-4-(c vanomethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyπolidinecar- boxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, and 9-ethyl-9Η-carbazol- 3-amine the title compound was obtained in 36% purity by LC/MS. MS(ΕSI+): m/z = 345.2.
Example 133: (2SAEZ)-1 -(4-cvanobenzoyl)-N-r2-(diethylammo ethvn-4-(methoχyimino)-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and Ν1,Ν1 -diethyl- 1,2-ethanediamine the title compoxmd was obtained in 58% purity by LC/MS. MS(ΕSI+): m/z = 386.2.
Example 134: 4- {r(2S.4EZ)-2-(lH-benzimidazol-2-yl -4-(cvanomethylene pyπolidinyl1- carbonyl)benzonitrile Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(cyanomethylene)-2-ρyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 1,2-benzenediamine the title compoxmd was obtained in 84% purity by LC/MS. MS(ΕSI+): m/z = 354.2.
Example 135: (2S.4E, )-4-[(allyloχy)immo]-l-r4-(dimethylamino)butanoyll-N-(9-ethyl-9H- carbazol-3-yl)-2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-4-[(allyl- oxy)imino]- 1 -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-(dimethylamino)-butanoyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 40% purity by LC/MS. MS(ΕSI+): m z = 490.4.
Example 136: (2S.4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl)-2-pyπolidinecarbox- amide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzyli- dene-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 53% purity by LC/MS. MS(ΕSI+): m/z = 396.2.
Example 137: (2S.4EZ)-4-benzylidene-l -r4-(dimethylamino)butanoyl]-N-(9-ethyl-9H-carba- zol-3-yl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzyli- dene- 1 -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 74% purity by LC/MS. MS(ΕSI+): m/z = 509.4.
Example 138: (2S.4EZ)-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-yl)-2-pyrrolidine- carboxamide Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, and 9-ethyl-9H-carbazol- 3-amine the title compoxmd was obtained in 73% purity by LC/MS. MS(ΕSI+): m/z = 354.4.
Example 139: (2S)-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from l-(tert-butoxycar- bonyl)-4-methyleneproline, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 71 % purity by LC/MS. MS(ESI+): m/z = 320.2.
Example 140: (2S-4EZ)-4-(cvanomethylene -N-(9-ethyl-9H-carbazol-3-ylVl-(4-phenoxy- benzoyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, 4-phenoxybenzoyl chlo-ride, and 9-ethyl-9Η-carbazol-3 -amine the title compoxmd was obtained in 37% purity by LC/MS. MS(ΕSI+): m/z = 541.4.
Example 141 : N-{[(2S,4EZ)-2-(lH-benzimidazol-2-yl)-4-(chloromethylene)pyπolidinyl]- carbonyllbenzamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, benzoyl isocyanate, and 1,2-benzenediamine the title compound was obtained in 51% purity by LC/MS. MS(ΕSI+): m/z = 381.4.
Example 142: (2S)-N1-(3,5-dichlorophenyl -N2-(9-ethyl-9H-carbazol-3-yl -4-methylene-l,2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, l,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9Η-carbazol-3- amine the title compoxmd was obtained in 40% purity by LC/MS. MS(ESI+): m/z = 507.6. Example 143 : (2S)- 1 -(diphenylacetyl -N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2-pyrro- lidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, diphenylacetyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 42% purity by LC/MS. MS(ESI+): m/z = 514.4.
Example 144: (2S.4EZ)-l-benzoyl-4-(chloromethylene)-N-(9-ethyl-9H-carbazol-3-vn-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, benzoyl chloride, and 9- ethyl-9Η-carbazol-3 -amine the title compound was obtained in 48% purity by LC MS. MS(ΕSI+): m/z = 458.4.
Example 145: (2SAEZ)- 1 -(\ 1.1 '-biphenyl] -4-ylcarbonyl -4-(c vanomethyleneVN-(9-ethyl-9H- carbazol-3-yl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, [l, -biphenyl]-4-carbonyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 32% purity by LC/MS. MS(ΕSI+): m/z = 525.4.
Example 146: (2S,4EZ)-4-(cyanomethylene -N-(9-ethyl-9H-carbazol-3-yl)-l-(3-oxobutyl')-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1 -(tert-but- oxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, 3-buten-2-one, and 9-ethyl- 9Η-carbazol-3-amine the title compoxmd was obtained in 59% purity by LC/MS. MS(ΕSI+): m/z = 415.2.
Example 147: (2S)-l-r(4-chlorophenoxy)acetyll-N-(9-ethyl-9H-carbazol-3-yl)-4-methylene-2- pyrrolidinecarboxamide Following the general method as outlined in Example 22, startmg from l-(tert-butoxycar- bonyl)-4-methyleneproline, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3- amine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m z = 488.4.
Example 148: (2S)-l-(ri '-biphenyll-4-ylcarbonyl)-N-(9-ethyl-9H-carbazol-3-yl')-4- methylene-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, [l,l'-biphenyl]-4-carbonyl chloride, and 9-ethyl-9Η-carbazol-3- a ine the title compoxmd was obtained in 46% purity by LC/MS. MS(ESI+): m/z = 500.4.
Example 149: 2-[(2S,4EZ)-4-(chloromethylene pyπolidinyl]-lH-benzimidazole
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, and 1,2-benzenediamine the title compound was obtained in 43% purity by LC/MS. MS(ΕSI+): m/z = 234.4.
Example 150: (2S.4EZ)-4-(ethoxyiminoVN-(9-ethyl-9H-carbazol-3-ylV2-ρvπolidine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 91% purity by LC/MS. MS(ΕSI+): m/z = 365.2.
Example 151: (2S -l-benzoyl-N-(9-ethyl-9H-carbazol-3-yl -4-methylene-2-pyrrolidine- carbox-amide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, benzoyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 52% purity by LC/MS. MS(ESI+): m/z = 424.2.
Example 152 : (2S,4EZ)-N-[2-(diethylamino)ethvn - 1 -(diphenylacetvD-4- (r(4-methoxyben- zyl)oxy]imino -2-pyrrolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]immo}-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and N1,N1 -diethyl- 1,2-ethanediamine the title compoxmd was obtained in 56% purity by LC/MS. MS(ΕSI+): m/z = 557.4.
Example 144153 (2S,4EZ -l-benzoyl-N-(2-furylmethylV4-(r(4-methoxybenzyl,oxy]-iminol- 2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(/ert-but- oxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, benzoyl chloride, and 2-furylmethylamine the title compound was obtained in 40% purity by LC/MS. MS(ΕSI+): m/z = 448.2.
Example 154: (2S.4EZ)-4-(tert-butoχyimmo)-N-[2-(diethylatnino)ethyl1-l-(diphenyl-acetyl)- 2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(tert-butoxyimino)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and Νl ,Νl-diethyl-l ,2-ethanediamine the title compound was obtained in 80% purity by LC/MS. MS(ΕSI+): m/z = 493.4.
Example 155: (2S)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl -N-(3,4-dimethoxybenzyl)-4-methylene-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, [l,l'-biphenyl]-4-carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z = 457.2.
Example 156: (2S.4EZ -4-(cvanomethylene -N1-(3.5-dichlorophenvn-N2-(9-ethyl-9H-carba- zol-3-yl - 2-pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, l,3-dichloro-5-isocyana- tobenzene, and 9-ethyl-9H-carbazol-3 -amine the title compound was obtained in 60% purity by LC/MS. MS(ESI+): m z = 532.8.
Example 157: (2S,4EZ)-4-r(allyloxy iminol-N2-(9-ethyl-9H-carbazol-3-vn-N1-phenyl-l 2- pyrrolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-
[(allyloxy)-iminoj- 1 -( ert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, isocyanato-benzene, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 67% purity by LC/MS. MS(ΕSI+): m/z = 496.4.
Example 158: (2S)-N -(9-ethyl-9H-carbazol-3 -yD-4-methylene-N1 -phenyl- 1.2- pyπolidinedicar-boxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, isocyanatobenzene, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 66% purity by LC/MS. MS(ESI+): m/z = 439.2.
Example 159: (2SAEZ)-N2-(2.1.3-benzothiadiazol-4-ylVN1-(3.5-dichlorophenylV4-(methoχy- imino)- 1 ,2-p vπolidinedicarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l~(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 1 ,3-dichloro-5-isocyanato- benzene, and 2,l,3-benzothiadiazol-4-amine the title compoxmd was obtained in 55% purity by LC/MS. MS(ESI+): m/z = 479.6.
Example 160: (2EZ)-[5-(lH-benzimidazol-2-yl)- 1 -(4-phenoxybenzoyl)-3-pyπolidinyli- dene] ethanenitrile
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l- tert- butoxycarbonyl)-4-(cyanomethylene)-2-pyπolidmecarboxylic acid, 4-phenoxybenzoyl chloride, and 1,2-benzenediamine the title compoxmd was obtained in 90% purity by LC/MS. MS(ΕSI+): m/z = 421.2. Examρle l61: (2S,4EZ)-4-(tert-butoxyimmoVl-(2-ethoχy-l-naphthoylVN-(9-ethyl-9H-carba- zol-3-yl)-2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(ter/-but- oxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidmecarboxylic acid, 2-ethoxy- 1 -naphthoyl chloride, and 9-ethyl-9Η-carbazol-3 -amine the title compound was obtained in 47% purity by LC/MS. MS(ΕSI+): m/z = 591.4.
Example 162: (2S,4EZ)-l-benzoyl-N-r2-(diethylammo ethyl]-4-(ethoxyimino -2-pyrroli- dinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and Ν1,Ν1- diethyl-l,2-ethanediamine the title compoxmd was obtained in 84% purity by LC/MS. MS(ΕSI+): m/z = 375.2.
Example 163: (ΣS EZ^-^^.l.S-benzothiadiazoM-yD^-f^enzyloxy minol-N^ henyl-l^- pyrrolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, isocyanatobenzene, and 2,l,3-benzothiadiazol-4-amine the title compound was obtained in 57% purity by LC/MS. MS(ΕSI+): m/z = 487.4.
Example 164 : (2SAEZ)- 1 -(4-cvanobenzoyl -4- \( .4-dichlorobenzyl)oxy]immo) -N-(l -naph- thylmethyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 1-naphthylmethylamine the title compoxmd was obtained in 39% purity by LC/MS. MS(ΕSI+): m/z = 571.6. Example 165: (2SAEZ)-N-(2Λ .3-benzo thiadiazol-4-yr)- 1 -benzoyl-4- ( [(4-methoxybenzyl - oxy1imino>-2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, benzoyl chloride, and 2,l,3-benzothiadiazol-4-amine the title compound was obtained in 61% purity by LC/MS. MS(ΕSI+): m/z = 502.4.
Example 166: (2S,4EZ>-4-r(allyloxy imino]-N-(2.1.3-benzothiadiazol-4-ylVl-(diphenylace- tyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 2,l,3-benzothiadiazol-4-amine the title compound was obtained in 46% purity by LC/MS. MS(ΕSI+): m/z = 512.4.
Example 167: (2S,4EZ)-4-(etiιoxyimmo)-N-(9-ethyl-9H-carbazol-3-yl l -f(2-oxo-6-ρentyl- 2H-pyran-3-yl)carbonyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compoxmd was obtained in 75% purity by LC/MS. MS(ΕSI+): m/z = 557.4.
Example 168: (2SAEZ)- 1 -benzoyl-4-(ethoxyimino -N-(9-ethyl-9H-carbazol-3-yl)-2-pyrro- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, benzoyl chloride, and 9-ethyl- 9Η-carbazol-3-amine the title compound was obtained in 74% purity by LC/MS. MS(ΕST+): m/z = 469.4. Example l69: (2S,4EZ)-4-(ethoxyimino -N-(9-ethyl-9H-carbazol-3-yl)-l-(methoxyacetylV2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, methoxyacetyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 88% purity by LC/MS. MS(ΕSI+): m/z = 437.2.
Example 170: (2S-4EZ -4-r(benzyloχy imino]-N2-(9-ethyl-9H-carbazol-3-yl)-N1-ρentyl-1.2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 1-isocyanato-pentane, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 540.4.
Example 171: (3EZ,5S -1 -benzoyl-5- { [4-(3 ,4-dichlorophenvD- 1 -piperazinyl] carbonyl) -3- pyπolidinone O-ethyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, benzoyl chloride, and l-(3,4- dichlorophenyl)piperazine the title compoxmd was obtained in 51% purity by LC/MS. MS(ΕSI+): m/z = 489.6.
Example 172: (2S.4EZ)-4-r(allyloxy imino1-N-(9-ethyl-9H-carbazol-3-yl -l- (2-oxo-6-pentyl- 2H-pyran-3-yl)carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-imino]-l -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η- pyran-3-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compoxmd was obtained in 48% purity by LC/MS. MS(ΕSI+): m/z = 569.4. Example 173 : (2S,4EZ)-4- {[(4-methoxybenzyl oxy]imino> -N-(2-methoxyethyl -2-pyπolidine- carboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, and 2- methoxyethylamine the title compound was obtained in 52% purity by LC/MS. MS(ΕSI+): m/z = 322.2.
Example 174: (2S.4EZ)-4-r(allyloxy immo1-N-(3.4-dimethoχybenzylVl-(diphenylacetvD-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 528.4.
Example 175: (2S.4EZ)-4-r(allyloxy imino1-l-(4-cvanobenzoylVN-(9-ethyl-9H-carbazol-3- yl)-2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-
[(allyloxy)-imino]-l ~(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 43% purity by LC/MS. MS(ΕSI+): m/z = 506.4.
Example 176: (2SAEZ)-4- { [(4-methoxybenzyl oxy]imino> -1 -[(2-oxo-6-pentyl-2H-pyran-3- yl)carbonyl]-N-(6-quinolmyl)-2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, 2-oxo-6- pentyl-2Η-pyran-3-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 61% purity by LC/MS. MS(ESI+): m/z = 583.4. Example l77: (2S.4EZ)-N-(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimmo -2-pyπolidinecar- boxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, and 9-ethyl-9Η-carbazol-3- amine the title compound was obtained in 46% purity by LC/MS. MS(ΕSI+): m/z = 351.2.
Example 178: (2S.4EZ)-N2-(9-ethyl-9H-carbazol-3-yl -4-(methoxyimino -NI-(3-methoxy- phenyl)-l,2-pyπolidinedicarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 1 -isocyanato-3- methoxybenzene, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 500.4.
Example 179: (2S.4EZ)-4-(ethoxyimino)-N2-(9-ethyl-9H-carbazol-3-yl)-N1-(3-methoxy- phenyD- 1 ,2-p yrrolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, l-isocyanato-3 -methoxybenzene, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 60% purity by LC/MS. MS(ΕSI+): m/z = 514.4.
Example 180: (2S.4EZ)-l-r(4-chloroρhenoχy^acetyl1-4-(ethoχyiminoVN-(9-ethyl-9H- carbazol-3-yl -2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compoxmd was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 533.4.
Example 181 : (2S.4EZ)-4-r(allyloχy')immo1-N-(9-ethyl-9H-carbazol-3-yl)-l-(4-phenoxy- benzoyl -2-pyπolidinecarboxamide - Ill -
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compoxmd was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 573.4.
Example 182: (2S.4EZ)-N1-benzoyl-N2-(9-ethyl-9H-carbazol-3-yl -4-(methoxyimino -l .2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, benzoyl isocyanate, and 9- ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 59% purity by LC/MS. MS(ΕSI+): m/z = 498.4.
Example 183 : (2S-4EZ)-4-r(benzyloxy imino1-N-(9-ethyl-9H-carbazol-3-vn-l-r(2-oxo-6- pentyl-2H-pyrap-3-yl)carbonyl]-2-pyrrolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(benzyloxy)imino]-l -(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-ρentyl-2Η- ρyran-3 -carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compoxmd was obtained in 93% purity by LC/MS. MS(ΕSI+): m/z = 619.6.
Example 184: (2S.4EZ)-l-acetyl-4-(ethoxyimino)-N-(9-ethyl-9H-carbazol-3-yl)-2-ρvπoli- dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, acetyl chloride, and 9-ethyl- 9Η-carbazol-3-amine the title compoxmd was obtained in 87% purity by LC/MS. MS(ΕSI+): m/z = 407.2.
Example 185: (2SAEZ)-l-(\\ ■r-biphenyl]-4-ylcarbonyl -4-(ethoxyimino -N-(9-ethyl-9H- carbazol-3-yl)-2-pyπolidinecarboxamide Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl] -4-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 70% purity by LC/MS. MS(ΕSI+): m z = 545.4.
Example 186: (2SAEZ)-\ -acetyl-N-(9-ethyl-9H-carbazol-3-vn-4-(methoxyimino -2-ρvπoli- dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, acetyl chloride, and 9-ethyl- 9Η-carbazol-3 -amine the title compoxmd was obtained in 69% purity by LC/MS. MS(ΕSI+): m/z = 393.2.
Example 187: (2S.4EZ)-l-(diphenylacetyl -N-(9-ethyl-9H-carbazol-3-vn-4-(methoχy-imino - 2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 9- ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 77% purity by LC/MS. MS(ΕSI+): m/z = 545.4.
Example 188: (2S.4EZ)-4-[(allyloxy iminol-Nϊ-benzoyl-N2-(9-ethyl-9H-carbazol-3-yl)- 2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, benzoyl isocyanate, and 9- ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 524.4.
Example 189: (2S,4EZ)-N -(9-ethyl-9H-carbazol-3-yl)-4-(methoxyimino -N1 -(3-methyl- phenvD- 1 ,2-pyπolidinedicarboxamide Follo ing the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1 -isocyanato-3-methylben- zene, and 9-ethyl-9H-carbazol-3 -amine the title compound was obtained in 89% purity by LC/MS. MS(ΕSI+): m/z = 484.4.
Example 190: (2S.4EZ)-4-(r(4-methoχybenzyl oxy]immo>-N1-pentyl-N2-(2-thienyl-methyl - 1 ,2-pyπolidmedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, 1- isocyanatopentane, and 2-thienylmethylamine the title compoxmd was obtained in 86% purity by LC/MS. MS(ΕSI+): m/z = 473.2.
Example 191 : (2S,4EZ)-4-(ethoxyimino')-l-(methoxyacetyl')-N-(6-quinolinyl -2-pyπo- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert~ butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, methoxyacetyl chloride, and 6-quinolinamine the title compound was obtained in 81% purity by LC/MS. MS(ΕSI+): m/z = 371.2.
Example 192: (2S-4EZ)-4-r(allyloxy imino1-N-(9-ethyl-9H-carbazol-3-ylV2-pyrrolidine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, and 9-ethyl-9Η- carbazol-3 -amine the title compound was obtained in 80% purity by LC/MS. MS(ΕSI+): m/z
= 377.2.
Example 193: (2S.4EZ)-4-r(benzyloχy)imino]-l-r(2-oxo-6-ρentyl-2H-pyran-3-yl carbonyll-N- (6-quinolinyl -2-pyπolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3- carbonyl chloride, and 6-quinolinamine the title compound was obtained in 48% purity by LC/MS. MS(ΕSI+): m/z = 553.4.
Example 194: (2S.4EZ)-4-[(allyloxy imipo]-N-r2-(diethylamino)ethyl1-2-ρvπolidine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, and Νl,Νl-diethyl- 1,2-ethanediamine the title compound was obtained in 78% purity by LC/MS. MS(ΕSI+): m/z = 283.0.
Example 195: (2SAEZ)- 1 -r4-(dimethylamino butano yl]-N-(9-ethvl-9H-carbazol-3-yI)-4- (methoxyimino -2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(dimethylamino)-butanoyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compound was obtained in 42% purity by LC/MS. MS(ΕSI+): m/z = 464.2.
Example 196: (2S)-2-[(3-hydroxy-l-azetidinyl)carbonyl]-N-(3-methoxyphenyl -4-oxo-l- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-oxoproline, l-isocyanato-3 -methoxybenzene, and 3-azetidinol the title compound was obtained in 87% purity by LC/MS. MS(ESI+): m/z = 334.2.
Example 197: (2S.4EZ)-4-[(benzyloxy)imino]-N-(9-ethyl-9H-carbazol-3-yl)-l-(phenoxyace- tyl -2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compoxmd was obtained in 65% purity by LC/MS. MS(ESI+): m/z = 561.4.
Example 198: (2S -N-(9-ethyl-9H-carbazol-3-ylV4-methylene-l -r(2-oxo-6-ρentyl-2H-pyran- 3 -vDcarbonyl] -2-p yπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, 2-oxo-6-pentyl-2Η-pyran-3-carbonyl chloride, and 9-ethyl-9H- carbazol-3-amine the title compoxmd was obtained in 70% purity by LC/MS. MS(ESI+): m/z = 512.4.
Example 199 : (2S.4EZV N-(9-ethyl-9H-carbazol-3-vD- 1 -(methoxyacetylV4-(methoxy-immo)- 2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 73% purity by LC/MS. MS(ΕSI+): m/z = 423.4.
Example 200: (2S,4EZ)-N2-(9-ethyl-9H-carbazol-3-ylV4-(methoxyiminoVN1 -ρentyl-1,2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimmo)-2-ρyπolidinecarboxylic acid, 1-isocyanatopentane, and 9- ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 81% purity by LC/MS. MS(ΕSI+): m/z = 464.2.
Example 201: (2S.4EZ)-4-(ethoxyimino -N1-pentyl-N2-r2-(lH-pyπol-l-yl ρhenvn-1.2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, 1-isocyanatopentane, and 2- (lH-pyrrol-l-yl)phenylamine the title compound was obtained in 83% purity by LC/MS. MS(ESI+): m/z = 426.2.
Example 202: (2S,4EZ)-4- (allyloxy immo]-N-(2-methoxyethyl -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, and 2-methoxyethyl-amine the title compound was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 242.0.
Example 203 : (2S.4EZ)-4-(tert-butoxyiminoVN -(2-methoχyethylVN1-("3-methoxyphenyl)- 1 ,2-pyπOlidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(tert-butoxyimmo)-2-pyπolidinecarboxylic acid, l-isocyanato-3 -methoxybenzene, and 2-methoxyethylamine the title compound was obtained in 76% purity by LC/MS. MS(ΕSI+): m/z = 407.2.
Example 204: (2S,4EZ)-4-r(allyloχy)iminol-N2-(2-methoxyethyl)-N1-(3-methylphenyl)-1.2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)-imino]- 1 -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 1 -isocyanato-3-methyl- benzene, and 2-methoxyethylamine the title compound was obtained in 85% purity by LC MS. MS(ΕSI+): m/z = 375.2.
Example 205 : (2S.4EZ)-;-benzoyl-4-benzylidene-N-(9-ethyl-9H-carbazol-3-ylV2-pyrroli- dinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-4-benzyli- dene-l-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 9-ethyl-9Η- carbazol-3-amine the title compoxmd was obtained in 81% purity by LC/MS. MS(ΕSI+): m/z = 500.4. Example 206: (2S.4EZ -N2-benzyl-4-benzylidene-N2-methyl-N1-(3-methylphenyl -1.2- pyπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzyli- dene- 1 -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 1 -isocyanato-3-methylbenzene, and Ν-benzyl-Ν-methylamine the title compoxmd was obtained in 68% purity by LC/MS. MS(ΕSI+): m/z = 440.2.
Example 207: (2S.4EZ)-4-(ethoxyimino -N-(9-ethyl-9H-carbazol-3-ylVl-(4-phenoxyben- zoyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 99% purity by LC/MS. MS(ΕSI+): m/z = 561.4.
Example 208: (2S,4EZ)-4-(ethoxyimino)-N2-(9-ethyl-9H-carbazol-3-vn-N1-(3-methyl- phenyl)- 1 ,2-p yπolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, 1 -isocyanato-3-methylben-zene, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 80% purity by LC/MS. MS(ΕSI+): m/z = 498.4.
Example 209 : (2S,4EZ -4-(methoxyimmoV 1 -(phenoxyacetylVN-(6-quinolinylV 2-pyπoli- dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and 6- quinolinamine the title compoxmd was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 419.2. Example 210: (2S-4EZ -4-(tert-butoxyimino -N-(3.4-dimethoxybenzyl -l-r(2-oxo-6-pentyl- 2H-pyran-3-yl)carbonyl]-2-ρyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2Η- pyran-3 -carbonyl chloride, and 3,4-dimethoxybenzylamine the title compoxmd was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 542.4.
Example 211: (2S,4EZ)-4-(tert-butoxyimino -N-cyclopropyl-l-(phenoxyacetyl)-2-pyrrolidine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(tert-butoxyimino)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and cyclopropylamme the title compound was obtained in 73% purity by LC/MS. MS(ΕSI+): m/z = 374.2.
Example 212: (2SAEZ)-4- (benz ylox y)imino] -N-(tert-but yl)- 1 -(phenox yacetyl)-2-pyrro- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxyQarbonyl)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and tert-butylamine the title compoxmd was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 424.2.
Example 213: (2S,4EZ)-N-(4-6-dimethoxy-2-ρyrimidinyl -4-(ethoxyimino)-l-(4-phenoxy- benzoyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 4,6-dimethoxy-2-ρyrimidinamine the title compound was obtained in 79% purity by LC/MS. MS(ΕSI+): m/z = 506.4. Example 214: (4ZE)-4-r(allyloxy immo]-N-(9-ethyl-9H-carbazol-3-yl -l-(ρhenoxyacetyl -2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-immo]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 63% purity by LC/MS. MS(ΕSI+): m/z = 511.4.
Example 215: (2S.4-5Z.-1 -ff 1.r-biphenyl1-4-ylcarbonvn-N-(9-ethyl-9H-carbazol-3-vn-4- (methoxyimino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [l,l'-biphenyl]-4-carbonyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 66% purity by LC/MS. MS(ΕSI+): m/z = 531.4.
Example 216: (3EZ,5S)- 1 -r4-(dimethylamino)butanoyl]-5-(l -piperidinylcarbonyl)-3-pyπo- lidinone O-methyloxime
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methρxyimino)-2-pyπolidinecarboxylic acid, 4-(dimethylamino)butanoyl chloride, and piperidine the title compoxmd was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 339.2.
Example 217: (2S.4EZ)-l-acetoacetyl-N-(9-ethyl-9H-carbazol-3-ylV4-(methoxyiminoV2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2,4-oxetanedione, and 9- ethyl-9Η-carbazol-3-amine the title compound was obtained in 42% purity by LC/MS. MS(ΕSI+): m/z = 435.2. Example 218: (2S.4EZ)-4-(methoxyimino)-l-r(2-oxo-6-ρentyl-2H-pyran-3-yl carbonyl1-N-(6- quinolmyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carbonyl chloride, and 6-quinolinamine the title compound was obtained in 57% purity by LC/MS. MS(ΕSI+): m/z = 477.2.
Example 219: (2S.4EZ)-N-(9-ethyl-9H-carbazol-3-yl -4-{r(4-methoxybenzvnoxy]iminol-l- r(2-oxo-6-pentyl-2H-p yran-3 -yPcarbonyl] -2-p vπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, 2-oxo-6- pentyl-2Η-pyran-3-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 57% purity by LC/MS. MS(ΕSI+): m/z = 649.4.
Example 220: (2S.4EZ)-N2-allyl-N1-benzoyl-4-(methoxyimino)-l ,2-pyrrolidinedicarbox-amide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, benzoyl isocyanate, and allylamine the title compound was obtained in 49% purity by LC/MS. MS(ΕSI+): m/z = 345.0.
Example 221 : (2S.4EZ)-4-r(benzyloxy mino]-N-(9-ethyl-9H-carbazol-3-yl)-l-(methoxy- acetyl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 46% purity by LC/MS. MS(ΕSI+): m z = 499.2.
Example 222: (2S.4EZ)-N1-(3.5-dichlorophenyl)-N2-(9-ethyl-9H-carbazol-3-yl)-4-(methoxy- imino)- 1 ,2-pyπolidinedicarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1 ,3-dichloro-5-isocyanato- benzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 42% purity by LC MS. MS(ΕSI+): m z = 538.2.
Example 223 : (2S.4EZ)-N-(9-ethyl-9H-carbazol-3-vn-4-(methoxyiminoVl -(4-phenoxyben- zoyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 43% purity by LC/MS. MS(ΕSI+): m/z = 547.2.
Example 224: (2S.4EZ)-N1-(3.5-dichlorophenylV4-(ethoxyimino)-N2-(9-ethyl-9H-carbazol-3- ylV 1 ,2-pynolidinedicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidmecarboxylic acid, 1 ,3-dichloro-5-isocyanato- benzene, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 43% purity by LC/MS. MS(ΕSI+): m/z = 552.6.
Example 225 : (3EZ.5S)-5- 4-(l .3-benzodioxol-5-ylmethylVl-piperazmvncarbonvU -1 -f (2- oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-3-pyπolidinone O-(tert-butyl oxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(/ert-butoxyimino)-2-pyπolidinecarboxyhc acid, 2-oxo-6-pentyl-2Η- ρyran-3 -carbonyl chloride, and l-(l,3-benzodioxol-5-ylmethyl)piperazine the title compound was obtained in 59% purity by LC/MS. MS(ΕSI+): m/z = 595.4.
Example 226: (2S.4EZ)-4-benzylidene-N-(9-ethyl-9H-carbazol-3-yl -l-r(2-oxo-6-pentyl-2H- pyran-3-yl carbonyl -2-pyπolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzyli- dene-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3- carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 47% purity by LC/MS. MS(ΕSI+): m/z = 588.4.
Example 227: (2S,4EZ)-4- (allyloxy)imino]- 1 -benzoyl-N-(6-quinolinyl)-2-pyrrolidine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)-immo]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, benzoyl chloride, and 6- quinolinamine the title compound was obtained in 83% purity by LC/MS. MS(ΕSI+): m/z = 415.2.
Example 228: (2S,4EZ)-4-[(allyloxy imino]-l-(methoxyacetyl -N-(6-quinolinyl)-2-pyπoli- dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, methoxyacetyl chloride, and 6-quinolinamine the title compound was obtained in 71% purity by LC/MS. MS(ΕSI+): m/z = 383.0.
Example 229: (2S.4EZ)-4-r(allyloxy)imino1-N-(9-ethyl-9H-carbazol-3-yl)-l-(methoxyacetylV 2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-4-[(allyl- oxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, methoxyacetyl chloride, and 9-ethyl-9Η-carbazol-3 -amine the title compoxmd was obtained in 74% purity by LC/MS. MS(ΕSI+): m z = 449.2.
Example 230: (2S,4EZ)-4-[(allyloxy imino]-l -(2-ethoxy-l -naphthoyl)-N-(9-ethyl-9H-carba- zol-3 -yl -2-ρyπolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-ethoxy-l-naphthoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 60% purity by LC/MS. MS(ΕSI+): m/z = 575.4.
Example 231 : (2S.4EZ)-4-[(allyloχy immo1-l-r(4-chlorophenoxy acetyl1-N-(9-ethyl-9H- carbazol-3-yl -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, (4-chlorophenoxy)acetyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 78% purity by LC/MS. MS(ΕSI+): m/z = 545.4.
Example 232: (2S.4EZ)-4-r(allyloxy imino]-l-(ri.r-biphenyl1-4-ylcarbonylVN-(9-ethyl-9H- carbazol-3-yl)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4- carbonyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 51% purity by LC/MS. MS(ΕSI+): m/z = 557.2.
Example 233 : (2S.4EZ)-4-r(allyloxy)imino]-l -(diphenylacetyl)-N-(9-ethyl-9H-carbazol-3-vn- 2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4- [(allyloxy)-imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and 9-ethyl-9Η-carbazol-3-amine the title compoxmd was obtained in 43% purity by LC/MS. MS(ΕSI+): m/z = 571.2.
Example 234: (2S,4EZ)-l-(n.r-biphenyl]-4-ylcarbonyl)-N-(tert-butyl)-4-(chloromethylene - 2-pyπolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbo-nyl chloride, and tert-butylamine the title compound was obtained in 80% purity by LC/MS. MS(ΕSI+): m/z = 397.6.
Example 235: tert-butyl 3-r(l4-methylene-l- (pentylamino carbonyl]-2-pyπolidinyl car- bonvDamino]- 1 -azetidinecarboxylate
Following the general method as outlined in Example 22, starting from l-(tert-butoxy- carbonyl)-4-methyleneproline, 1-isocyanatopentane, and tert-butyl 3 -amino- 1 -azetidinecarboxylate the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z = 395.2.
Example 236: (3EZ,5S)-l-acetyl-5- (4-acetyl-l-piperazinyl carbonyll-3-pyπolidinone O-(3,4- dichlorobenzyl oxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(3,4-dichlorobenzyl)oxy]imino} -2-ρyπolidinecarboxylic acid, acetyl chloride, and 1-acetylpiρerazine the title compoxmd was obtained in 85% purity by LC/MS. MS(ΕSI+): m/z = 455.2.
Example 237: (2S,4EZ)-N2-bepzyl-4-(methoxyimino)-N1-pentyl-l ,2-pyπolidmedicarbox- amide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 1-isocyanatopentane, and benzylamine the title compound was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 361.0.
Example 238: (2S.4EZ)-l-acetyl-4-{r(3.4-dichlorobenzyl)oχy]iminol-N-(l-naphthyl-methylV 2-pyπolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, acetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 60% purity by LC/MS. MS(ΕSI+): m/z = 484.2.
Example 239: (2S.4EZ)-4-(tert-butoxyimino -N-cycloρropyl-l-r(2-oxo-6-pentyl-2H-ρyran-3- yl carbonyl]-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(tert-butoxyimino)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η- pyran-3 -carbonyl chloride, and cyclopropylamme the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z = 432.2.
Example 240: (2S.4EZ)-4-{r(4-methoxybenzvπoxy]imino>-l-(4-phenoxybenzoylVN-r2-(lH- p vπol- 1 -vDphenyl] -2-p yπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, 4-phenoxy- benzoyl chloride, and 2-(lΗ-ρyπol-l-yl)phenylamine the title compoxmd was obtained in 55% purity by LC/MS. MS(ΕSI+): m/z = 601.4.
Example 241 : (2S -N-(l,3-benzodioxol-5-ylmethyl)-4-oxo-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-oxoproline, and l,3-benzodioxol-5-ylmethylamine the title compoxmd was obtai-ned in 71% purity by LC/MS. MS(ESI+): m/z = 263.0.
Example 242: (2S.4EZ)-N-(1.3-benzodioxol-5-ylmethyl -l-([ l'-biphenyl]-4-ylcarbonvn-4- (chloromethylene -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbo-nyl chloride, and l,3-benzodioxol-5-ylmethylamine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z = 475.6.
Example 243 : (2S.4EZ)-N-(3.4-dimethoxybenzvn-4-(ethoxyimino -l-[(2-oxo-6-pentyl-2H- pyran-3-yl)carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carbonyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 41% purity by LC/MS. MS(ΕSI+): m/z = 514.2.
Example 244: (2S)-2-[(3-hydroxy-l-azetidinyl)carbonyl1-N-(3-methylphenyl -4-oxo-l- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-oxoproline, l-isocyanato-3 -methylbenzene, and 3-azetidinol the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z = 318.0.
Example 245 : (2S,4EZ)-4-r(be-izyloxy imino]-N-r(2RS -2-hvdroxy-2-phenethyl1-l -IY2-oxo-6- pentyl-2H-pyran-3-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-pyran-3- carbonyl chloride, and (li?S)-2-amino-l-phenylethanol the title compoxmd was obtained in 55% purity by LC/MS. MS(ΕSI+): m/z = 546.2.
Example 246: (2S.4EZ)-4-r(allyloxy imino]-N2-(3.4-dimethoxybenzyl -N1-(3-methoxy- phenvD- 1 ,2-pyrrolidinedicarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-4-[(allyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, l-isocyanato-3 -methoxybenzene, and 3,4-dimethoxybenzylamine the title compound was obtained in 97% purity by LC/MS. MS(ΕSI+): m/z = 483.2. Example 247: (2S-4EZ -4-r(allyloxy imino]-l-(4-cyanobenzoylVN-(2-methoxyethyl -2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-cyanobenzoyl chloride, and 2-methoxyethylamine the title compoxmd was obtained in 44% purity by LC/MS. MS(ΕSI+): m/z = 371.0.
Example 248 : (2S,4EZ)-N-benzyl- 1 -(methoxyacetyl)-4- { [(4-methoxybenzyl)oxy]imino) -2- pyπolidine-carboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, methoxyacetyl chloride, and benzylamine the title compound was obtained in 49% purity by LC/MS. MS(ΕSI+): m/z = 426.2.
Example 249: (2S,4EZ)-l-benzoyl-4-(chloromethylene)-N-(2-furylmethyl)-2-pyrrolidine- carboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, benzoyl chloride, and 2- furylmethylamine the title compoxmd was obtained in 73% purity by LC/MS. MS(ΕSI+): m/z = 345.6.
Example 250: (2S)-l-acetyl-4-methylene-N-(6-quinolinyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, acetyl chloride, and 6-quinolinamine the title compoxmd was obtained in 87% purity by LC/MS. MS(ESI+): m/z = 296.0.
Example 251: (2S.4EZ)-l-acetyl-4-{r(3.4-dichlorobenzyl)oxylimino)-N-(2-furylmethylV2- pyπolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, acetyl chloride, and 2-furylmethylamine the title compound was obtained in 199% purity by LC/MS. MS(ΕSI+): m/z = 424.6.
Example 252: (2S)-N1-(3.5-dichlorophenylV4-methylene-N2-(6-quinolinylV1.2-pyπoli- dinedicarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxy-car- bonyl)-4-methyleneρroline, l,3-dichloro-5-isocyanatobenzene, and 6-quinolinamine the title compound was obtained in 65% purity by LC/MS. MS(ESI+): m/z = 441.0.
Example 253: (3EZ,5S)-l-(diphenylacetyl)-5-(l-piperidinylcarbonyl)-3-pyrrolidinone O-(4- metfaoxybenzypoxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(ter/-but- oxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, diphenylacetyl chloride, and piperidine the title compoxmd was obtained in 87% purity by LC/MS. MS(ΕSI+): m/z = 526.4.
Example 254: (2S.4EZ)-4-(chloromethylene)-N-(l-naphthylmethyl)-l-(phenoxyacetyl -2- pyπolidine-carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 75% purity by LC/MS. MS(ΕSI+): m/z = 435.6.
Example 255: (2S,4EZ)-4-r(allyloxy)imino]-N-benzoyl-2-(4-morpholinylcarbonyl)-l-pyrro- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπohdinecarboxylic acid, benzoyl isocyanate, and morpholine the title compoxmd was obtained in 46% purity by LC/MS. MS(ESI+): m/z = 401.2.
Example 256: (2S,4EZ)-NI-benzoyl-4-(chloromethylene -N2-cvclopropyl-l,2-pyπolidine- dicarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)~l-(tert- butoxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, benzoyl isocyanate, and cyclopropylamme the title compound was obtained in 76% purity by LC/MS. MS(ESI+): m/z = 348.6.
Example: 257: (2S,4EZ)-4-(r(3.4-dichlorobenzvPoχy]immo)-l-(methoχyacetylVN-(l- naphthylmethyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycafbonyl)-4- { [(3 ,4-dichlorobenzyl)oxy]imino} -2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 1-naphthylmethylamine the title compoxmd was obtained in 91% purity by LC/MS. MS(ΕSI+): m/z = 514.8.
Example 258: (2SAEZ)- 1 -benzoyl-N-benzyl-4-(chloromethylene)-N-methyl-2-pyrrolidine- carboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(chloromethylene)-2-pyπolidinecarboxylic acid, benzoyl chloride, and Ν- benzyl-Ν-methylamine the title compound was obtained in 62% purity by LC/MS. MS(ΕSI+): m/z = 369.4.
Example 259: (2S)-N2-(2-furylmethyl -N1-(3-methoχyρhenylV4-methylene-l .2-pyπolidine- dicarboxamide
Following the general method as outlined in Example 22, startmg from l-(tert-butoxycar- bonyl)-4-methyleneproline, l-isocyanato-3-methoxybenzene, and 2-furylmethylamine the title compound was obtained in 95% purity by LC/MS. MS(ESI+): m/z = 356.0. Example 260: (3EZ,5S)-5- (4-benzhydryl-l-piρerazinyl)carbonyn-l-(phenoxyacetyl)-3- pyπolidinone O-ethyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and 1 -benzhydrylpiperazine the title compound was obtained in 67% purity by LC/MS . MS(ΕSI+) : m/z = 541.2.
Example 261: (3EZ,5S)-l-benzoyl-5-(4-morpholinylcarbonyl -3-pyπolidinone Q-(3A- dichlorobenzvD-oxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, benzoyl chloride, and morpholine the title compoxmd was obtained in 69% purity by LC/MS. MS(ΕSI+): m/z = 476.2.
Example 262: (2S -N1-(3-methoxyphenyl')-4-methylene-N2-(l-naphthylmethyl -1.2- pyπolidine-dicarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxy- carbonyl)-4-meth-yleneproline, l-isocyanato-3-methoxybenzene, and 1-naphthylmethyl-amine the title compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z = 416.3.
Example 263: N2-(2-methoxyethyl)-4-methylene-N1-(3-methylphenyl)-l,2-pyrrolidinedi- carboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, l-isocyanato-3-methylbenzene, and 2-methoxyethylamine the title compound was obtained in 85% purity by LC/MS. MS(ESI+): m/z = 318.0.
Example 264: (2S,4EZ)-N-allyl-4-( (4-methoχybenzvπoxy1iminol-l-(ρhenoxyacetylV2- pyrrolidinecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4- {[(4-methoxybenzyl)oxy]imino} -2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and allylamine the title compoxmd was obtained in 72% purity by LC/MS. MS(ΕSI+): m/z = 438.2.
Example 265 : (2S,4EZ)-l-benzoyl-4-(cyanomethylene)-N-(l-naphthylmethyl -2-pyπoli- dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(cyanomethylene)-2-pyπolidinecarboxylic acid, benzoyl chloride, and 1- naphthylmethylamine the title compoxmd was obtained in 43% purity by LC/MS. MS(ESI+): m/z = 396.0.
Example 266 : (2SAEZ)-4- ξ\( .4-dichlorobenzyl)oxy1imino) - 1 -r(2-oxo-6-pentyl-2H-ρyran-3- yl)carbonyl1-N-(6-quinolinylV2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, 2-oxo-6- pentyl-2Η-pyran-3-carbonyl chloride, and 6-quinolinamine the title compoxmd was obtained in 70% purity by LC/MS. MS(ΕSI+): m/z = 621.2.
Example 267: (2S.4EZ)-N-r2-(diethylamino ethyl1-l-r4-(dimethylamino butanoyl1-4-{r(4- methoxybenzyl)oxy]imino ) -2-p yrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyπolidinecarboxylic acid, 4-
(dimethylamino)butanoyl chloride, and Ν1,Ν1 -diethyl- 1,2-ethanediamine the title compound was obtained in 100% purity by LC/MS. MS(ΕSI+): m/z = 476.2.
Example 268: (2S.4EZ)-4-r(allyloxy immo]-l-r4-(dimethylamino)butanoyl1-N-(l-naρhthyl- methyl)-2-pyπolidmecarboxamide Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)imino]- 1 -(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 4-(dimethylamino)buta-noyl chloride, and 1-naphthylmethylamine the title compoxmd was obtained in 85% purity by LC/MS. MS(ΕSI+): m/z =437.2.
Example 269: (2S.4EZ)-N-[2-(diethylamino)ethyl]-4-(ethoxyimino -2-pyπolidinecarbox- amide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, and Νl,Νl-diethyl-l,2- ethanediamine the title compoxmd was obtained in 70% purity by LC/MS. MS(ΕSI+): m/z = 271.0.
Example 270: (2S -4-methylene-l-r(2-oxo-6-pentyl-2H-pyran-3-vDcarbonyl1-N-(6- qumolinyl)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from l-(tert-butoxycar- bonyl)-4-methyleneproline, 2-oxo-6-pentyl-2Η-pyran-3 -carbonyl chloride, and 6-quinoli- namine the title compound was obtained in 48% purity by LC/MS. MS(ESI+): m/z = 446.2.
Example 271 : (2S.4EZ)-l-acryloyl-N-allyl-4-(methoxyimipo)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, acryloyl chloride, and allylamine the title compoxmd was obtained in 81% purity by LC/MS. MS(ΕSI+): m/z = 252.0.
Example 273: tert-butyl 3-({[(2S,4EZH-acetyl-4-benzylidenepwolidinyl] carbonyl) -amino)- 1 -azetidinecarboxylate
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzyli- dene-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, acetyl chloride, and tert-butyl 3- amino-1 -azetidinecarboxylate the title compoxmd was obtained in 81% purity by LC/MS. MS(ΕSI+): m/z = 400.2. Examρle 273: (2S.4EZ)-4- (allyloxy imino]-l-[(2-oxo-6-pentyl-2H-ρyran-3-yDcarbonv -N- (6-quinolinyl -2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyl- oxy)imino]-l-(tert-butoxycarbonyl)-2-pyπolidinecarboxylic acid, 2-oxo-6-pentyl-2Η-ρyran-3- carbonyl chloride, and 6-quinolinamine the title compoxmd was obtained in 67% purity by LC/MS. MS(ΕSI+): m/z = 503.2.
Example 274: (2S.4EZ)-4-(ethoχyimino -N-(l-naphthylmethyl)-l-(phenoxyacetyl)-2-pyπo- lidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert-but- oxycarbonyl)-4-(ethoxyimino)-2-pyπolidinecarboxylic acid, phenoxyacetyl chloride, and 1- naphthylmethylamine the title compoxmd was obtained in 85% purity by LC/MS. MS(ΕSI+): m/z = 446.3.
Example 275: (2S.4EZ)-N-|~(2i,S)-2-hvdroχy-2-ρhenylethyl]-4-(methoχyimino)-l-r(2'- methyl[ 1 , 1 '-biphenyl] -4-yl carbonyl] -2-p vπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[ 1 , 1 '-biphenyl]-4- carboxylic acid, and (li?S)-2-amino-l-phenylethanol, the title compoxmd was obtained in 96.4 % purity by HPLC. MS(ΕSI+): m/z = 472.
Example 276: (2S,4EZ)-l-(r r-biphenvn-3-ylcarbonvn-N-r(2RS)-2-hydroxy-2-phenyl-ethyl]- 4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -3 -carboxylic acid, and (lRS)-2-amino-l-phenylethanol, the title compoxmd was obtained in 72 % purity by HPLC. MS(ΕSI+): m/z = 458. Example 277: (2S.4EZ)-l-(4-benzoylbenzoylVN-r(2RS)-2-hvdroxy-2-phenylethyl1-4- (methoxyimino)-2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-benzoylbenzoic acid, and (lRS)-2-amino-l-phenylethanol, the title compoxmd was obtained in 93 % purity by HPLC. MS(ΕSI+): m/z = 486.
Example 278: (2S.4EZ)-N-[(2RS)-2-hvdroxy-2-phenylethyl] 4-(methoxyimino)-l-(3- phenoxybenzoyl)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 3-ρhenoxybenzoic acid, and (lRS)-2-amino-l-phenylethanol, the title compound was obtained in 94 % purity by HPLC. MS(ESI+): m/z = 474.
Example 279: (2S.4EZ)-N-r(2RS -2-hvdroxy-2-phenylethyl]-4-(methoxyiminoVl-(2- phenoxybenzoyl -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2-phenoxybenzoic acid, and (lRS)-2-amino-l-phenylethanol, the title compound was obtained in 92 % purity by HPLC. MS(ΕSI+): m/z = 474.
Example 280: (2S.4EZ)-N-r(2S)-2-hvdroxy-2-ρhenylethyl1-4-(methoxyimino -l-r(2'- methylf 1 , 1 '-biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-ϊ-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and (lS)-2-amino-l-phenylethanol, the title compoxmd was obtained in 98 % purity by HPLC. MS(ΕSI+): m/z = 472. Example 281 : (2S-4EZ)-N-r(2R -2-hvdroxy-2-phenylethyl]-4-(methoxyiminoVl-[(2'- methyl[l, -biphenyl]-4-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-py_τolidinecarboxylic acid, 2'-methyl[l,l -biphenyl] -4- carboxylic acid, and (li?)-2-amino-l-phenylethanol, the title compound was obtained in 84 % purity by HPLC. MS(ΕSI+): m/z = 472.
Example 282: (2S.4EZ)-N-(2-hydroxyethyl)-4-(methoχyimino)-l-r(2'-methviriJ'-biphenyl1-4- yl carbonyl]-2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and 2-aminoethanol, the title compoxmd was obtained in 75 % purity by HPLC. MS(ΕSI+): m/z = 396.
Example 283: (2S.4EZ)-N-(2-hvdroxyethylV4-(methoxyiminoVN-methyl-l-r(2'-methyl-n.l'- biphenyl]-4-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[ 1,1 '-biphenyl] -4- carboxylic acid, and 2-(methylamino)ethanol, the title compoxmd was obtained in 78 % purity by HPLC. MS(ΕSI+): m/z = 410.
Example 284: (2SAEZ)- 1 -ff U '-biphenyl1-4-ylsulfonvn-N-r(lS.2S.3R.4R -3-(hvdroxy- methvDbic yclo [2.2.1 ]hept-2-yl] -4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1 ,l'-biphenyl]-4-sulfonyl chloride, and [(li?,2i?,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title compoxmd was obtained in 79 % purity by HPLC. MS(ΕSI+): m/z = 498. Example 285: (2SAEZ)-l-(\l ,1 '-biphenyl] -4-ylcarbonyl -N-(trα»5-4-hvdroxycyclohexylV4- (methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1 ,l'-biphenyl]-4-carbonyl chloride, and trøns-4-aminocyclohexanol, the title compoxmd was obtained in 62 % purity by HPLC. MS(ΕSI+): m/z = 436.
Example 286: (2S.4EZ)-l-(r r-biphenyl]-4-ylcarbonylVN-[(lR.2R -2-(hvdroxymethylV cvclohexyl]-4-(methoxyimmo)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and [(li-,2R)-2-aminocyclohexyl]methanol, the title compoxmd was obtained in 65 % purity by HPLC. MS(ΕSI+): m/z = 450.
Example 287: (2S.4EZ)-l-(ri.l'-biphenyl1-4-ylcarbonvn-N-r(2RS -2-hvdroχy-3- phenoxypropyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyiminQ)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (2RS)-l-amino-3-phenoxy-2-ρropanol, the title compound was obtained in 68 % purity by HPLC. MS(ΕSI+): m/z = 488.
Example 288: (2S.4EZ -N-r(2RS)-2-hydroxy-3-ρhenoχyproρyl1-4-(methoxyimino')-l-r4-(3- pyridinyl benzoyl]-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (2RS)-l-amino-3-phenoxy-2-ρropanol, the title compoxmd was obtained in 76 % purity by HPLC. MS(ΕSI+): m/z = 489. Examρle 289: (2S,4EZ)-l-(r l'-biphenyl1-4-ylsulfonyl -N-[(2RS)-2-hvdroxy-3-phenoxy- propyl] -4-(methoxyimino)-2 -pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-ρyπolidinecarboxylic acid, [l,l'-biphenyl]-4-sulfonyl chloride, and (2RS)-l-amino-3-phenoxy-2-propanol, the title compoxmd was obtained in 78 % purity by HPLC. MS(ΕSI+): m/z = 524.
Example 290: (2SAEZ)- \l .l'-biphenyl]-4-ylcarbonylVN-r(2RS -2-hvdroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and 4-[(lRS)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 63 % purity by HPLC. MS(ΕSI+): m/z = 474.
Example 291: (2S,4EZ -l-([l.l'-biphenyl]-4-ylsulfonylVN-r(2RS -2-hvdroχy-2-(4- hydroxyphenyπethyl]-4-(methoχyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and 4-[(lRS)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 72 % purity by HPLC. MS(ΕSI+): m/z = 510.
Example 292: (2SAEZ)-l -(IT .1 '-biphenyl]-4-ylcarbonyl -N- (l -hvdroxycvclohexyD-methyl]- 4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecafboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and l-(aminomethyl)cyclohexanol, the title compound was obtained in 65 % purity by HPLC. MS(ΕSI+): m/z = 450. Example 293: (2S,4EZ)-N- (l-hydroxycvclohexyl methyl]-4-(methoxyimino)-l-r4-(3- pyridinyl)benzoyl]-2-ρyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and l-(aminomethyl)cyclohexanol, the title compound was obtained in 69 % purity by HPLC. MS(ΕSI+): m/z = 451.
Example 294 : (2SAEZ)- 1-qi.l '-biρhenyl1-4-ylsulfonyl)-N-r( 1 -hvdroxycyclohexyl)methyl1-4- (methoxyimmo)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and l-(aminomethyl)cyclohexanol, the title compound was obtained in 66 % purity by HPLC. MS(ESI+): m/z = 486.
Example 295: (2S.4EZ)-l-(ria'-biphenyl]-4-ylcarbonylVN-[(2RS -2-(3.4-dihvdroxy-phenvn- 2-hydroxyethyn-4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and 4-[(li?S)-2-amino-l-hydroxyethyl]-l,2-benzenediol, the title compoxmd was obtained in 66 % purity by HPLC. MS(ΕSI+): m/z = 490.
Example 296: (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino -l-r4-(4- pyridinyl)benzoyl]-2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and (lS)-2-amino-l-ρhenylethanol, the title compoxmd was obtained in 65 % purity by HPLC. MS(ΕSI+): m/z = 459. Example 297: (2S.4EZ)-N-r(2S)-2-hydroxy-2-phenylethvn-4-(methoxyiminoVl-r4-(3- pyridinyl)bepzoyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (lS)-2-amino-l -phenylethanol, the title compound was obtained in 73 % purity by HPLC. MS(ΕSI+): m/z = 459.
Example 298: (2S.4EZ)-N-r(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino -l-r4-(2- pyridinyl)benzoyl]-2-pyπoli dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(2-ρyridinyl)benzoic acid, and (lS)-2-amino-l -phenylethanol, the title compoxmd was obtained in 69 % purity by HPLC. MS(ESI+): m/z = 459.
Example 299: (2S.4EZ^-l-(riJ'-biphenyl1-4-ylcarbonylVN-r(2R,y)-2.3-dihvdroχypropyl]-4- (methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [l,l'-biphenyl] -4-carbonyl chloride, and (2RS)-3-amino-l,2-ρropanediol, the title compound was obtained in 73 % purity by HPLC. MS(ΕSI+): m/z = 412.
Example 300: (2S.4EZ)-l-(ri.l'-biphenyl]-4-ylsulfonvn-N-r(2RS)-2,3-dihydroxypropyl]-4- (methoxyimino -2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (2RS)-3-amino-l,2-propanediol, the title compoxmd was obtained in 64 % purity by HPLC. MS(ΕSI+): m/z = 448. Example 301 : (2S.4EZ)-l-([l,l,-biphenyl]-4-ylcarbonyl -N-[(2RS)-2-hvdroxy-3-(4- methoxyphenoxy propyl]-4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [l,l'-biphenyl]-4-carbonyl chloride, and (2RS)-l-amino-3-(4-methoxyphenoxy)-2-propanol, the title compoxmd was obtained in 81 % purity by HPLC. MS(ΕSI+): m/z = 518.
Example 302: (2S.4EZ)-N-r(2RS)-2-hvdroxy-3-(4-methoxyphenoxy)propyl1-4-(methoxy- imino - 1 -[4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (2RS)-l-amino-3-(4-methoxyphenoxy)-2-propanol, the title compoxmd was obtained in 63 % purity by HPLC. MS(ΕSI+): m/z = 519.
Example 303: (2S.4EZ)-l-(ri.r-biphenyl]-4-ylsulfonylVN-r(2RS)-2-hvdroχy-3-(4- methoxyphenoxy propyl1-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-ρyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (2RS)-l-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound was obtained in 69 % purity by HPLC. MS(ΕSI+): m/z = 554.
Example 304: (2S.4EZ)-l-(r r-biphenvn-4-ylcarbonyl)-N-r(2RS)-2-hvdroχypropyn-4- (methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and (2RS)-l-amino-2-propanol, the title compoxmd was obtained in 82 % purity by HPLC. MS(ΕSI+): m/z = 396. Example 305 : (2SAEZ)-U\ 1 , 1 '-biphenyl]-4-ylsulfonyl -N-r(2i?S -2-hvdroxypropyl]-4- (methoxyimino)-2-pyrroli dinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (2RS)-1 -amino-2-propanol, the title compoxmd was obtained in 75 % purity by HPLC. MS(ΕSI+): m/z = 432.
Example 306: (2S.4EZ)-l-(ria'-biphenyl1-4-ylsulfonyl)-N-[(2RS)-2-hvdroxy-2-(2- naphthyl)ethyl]-4-(methoχyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4E2)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (lRS)-2-amino-l-(2-naphthyl)ethanol, the title compoxmd was obtained in 77 % purity by HPLC. MS(ΕSI+): m/z = 544.
Example 307: (2S.4EZ)-l-(ri.l'-biphenyl]-4-ylcarbonylVN-r(2RS)-2-hvdroxy-2-(4- nitrophenyl ethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (li?S)-2-amino-l-(4-nitrophenyl)ethanol, the title compoxmd was obtained in 84 % purity by HPLC. MS(ESI+): m/z = 503.
Example 308: (2S,4EZ)-N-r(2RS)-2-hvdroχy-2-(4-nitrophenynethyl]-4-(methoxyimino)-l-r4- (4-pyridmyl benzoyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and (lR_S)-2-amino-l-(4-nitrophenyl)ethanol, the title compound was obtained in 89 % purity by HPLC. MS(ΕSI+): m/z = 504. Examρle 309: (2S-4EZ -N-r(2J?S)-2-hvdroxy-2-(4-nitrophenvnethyl]-4-(methoxyimino -l-r4- (3 -p yridinvDbenzo yl] -2-ρyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (lR5)-2-ammo-l-(4-nitrophenyl)ethanol, the title compoxmd was obtained in 72 % purity by HPLC. MS(ΕSI+): m/z = 504.
Example 310: (2S-4EZ)-N-[(2i?S)-2-hvdroxy-2-(4-nitrophenyl)ethyl1-4-(methoxyiminoVl-f4- (2-pyridinyl benzoyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l- tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(2-pyridinyl)benzoic acid, and (lΛS)-2-amino-l-(4-nitrophenyl)ethanol, the title compound was obtained in 63 % purity by HPLC. MS(ESI+): m/z = 504.
Example 311: (2S.4EZ)-l-(ri.r-biphenyl1-4-ylsulfonylVN-r(2i?S)-2-hvdroxy-2-(4- nitrophenyl)ethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (lRS)-2-ammo-l-(4-nitrophenyl)ethanol, the title compoxmd was obtained in 79 % purity by HPLC. MS(ΕSI+): m/z = 539.
Example 312: (2S.4EZ)-N-{(2RS)-3-r4-(acetylamino)ρhenoxy]-2-hvdroxyproρyl)-l-(ri.l'- biphenyn-4-ylcarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, andN-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the title compound was obtained in 79 % purity by HPLC. MS(ΕSI+): m/z = 545. Example 313: (2SAEZ)-N- ((2RS)-3-r4-(acetylamino)phenoxy]-2-hvdroxypropyl) -4- (methoxyimino)- 1 - 4-(4-p yridinvDbenzoyl] -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and N-(4- {[(2RS)-3-amino-2-hydroxypropyl]oxy} phenyl) acetamide, the title compoxmd was obtained in 62 % purity by HPLC. MS(ΕSI+): m/z = 546.
Example 314: (2SAEZ)-N- {(2RS)-3-r4-(acetylamino)ρhenoxyl-2-hvdroxypropyl)-4- (methoχyimino)-l-[4-(3-pyridinyl)benzoyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, 4-(3-pyridmyl)benzoic acid, and N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy} phenyl) acetamide, the title compoxmd was obtained in 66 % purity by HPLC. MS(ESI+): m/z = 546.
Example 315: (2S.4EZ>-N-((2RS)-3-r4-(acetylamino')phenoxy]-2-hvdroxypropyl)-l-(fia'- biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl] -4-sulfonyl chloride, and N-(4-{[(2i-S)-3-amino-2-hydroxypropyl]oxy} phenyl) acetamide, the title compound was obtained in 62 % purity by HPLC. MS(ΕSI+): m/z = 581.
Example 316: (2S.4EZ)-l-(ri.r-biphenyl1-4-ylcarbonyl -N-r(2RV2-hvdroxy-2-ρhenylethyl]-4- (methoxyimino)-2-py-τolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (li?)-2-amino-l -phenylethanol, the title compound was obtained in 84 % purity by HPLC. MS(ΕSI+): m/z = 458. Example 317: (2S,4EZ)-N-[(2R -2-hvdroxy-2-phenylethyll-4-(methoxyimino -l -f4-(4- ρyridmyl benzoyl1-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and (lR)-2-amino-l-phenylethanol, the title compoxmd was obtained in 66 % purity by HPLC. MS(ΕSI+): m/z = 459.
Example 318: (2S.4EZ)-N-r(2R -2-hvdroxy-2-phenylethyl1 -4-(methoxyiminoV 1 -T4-(3- pyridinyl)benzoyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (lR)-2-amino-l-phenylethanol, the title compound was obtained in 76 % purity by HPLC. MS(ΕSI+): m/z = 459.
Example 319: (2S.4EZ -N-r(2i?V2-hvdroxy-2-phenylethyl]-4-(methoxyimino)-l-r4-(2- pyridinyl)benzoyl1-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(2-pyridinyl)benzoic acid, and (lR)-2-amino-l -phenylethanol, the title compound was obtained in 65 % purity by HPLC. MS(ΕSI+): m/z = 459.
Example 320: (2SAEZ)- \1 , 1 '-biphenyl1-4-ylsulfonyl -N-r(2i?)-2-hydroxy-2-ρhenyl-ethyl1- 4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (lR)-2-amino-l-phenylethanol, the title compound was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 494. Example 321: (2SAEZ)- 1 -([1.1 '-biphenyl1-4-ylcarbonyl)-N-(3-hvdroxyρropyl)-4-(methox v- immo)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and 3-amino-l-propanol, the title compound was obtained in 81 % purity by HPLC. MS(ΕSI+): m/z = 395.
Example 322: (2SAEZ)-l-(\ 1.1 '-biphenyn-4-ylsulfonyl)-N-(3-hvdroχypropyn-4-(methoχy- immo)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and 3-amino-l-propanol, the title compoxmd was obtained in 64 % purity by HPLC. MS(ΕSI+): m/z = 432.
Example 323: (3EZ.5S -l-(riJ'-biρhenyl]-4-ylcarbonyl)-5-r(4-hvdroxy-4-phenyl-l-piρeri- dinvDcarbonyl] -3 -pyπolidinone O-methyloxime
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [l,r-biphenyl]-4-carbonyl chloride, and 4-ρhenyl-4-piperidinol, the title compoxmd was obtained in 74 % purity by HPLC. MS(ESI+): m/z = 498.
Example 324: (3EZ,5S -5-[(4-hydroxy-4-phenyl-l-piperidinyl)carbonyl]-l-[4-(4-pyri- dinyl)benzoyl]-3-pyrrolidmope O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and 4-phenyl-4-piperidinol, the title compound was obtained in 78 % purity by HPLC. MS(ΕSI+): m/z = 499. Example 325 : (3EZ,5S)-5-r(4-hydroxy-4-phenyl- 1 -piperidinvDcarbonyl]- 1 -[4-(3-pyridi- nvDbenzo yl] -3 -pyrrolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and 4-phenyl-4-piperidinol, the title compoxmd was obtained in 79 % purity by HPLC. MS(ΕSI+): m/z = 499.
Example 326: (3EZ.5S -l-([l,r-biphenyl]-4-ylsulfonyl -5- (4-hvdroxy-4-phenyl-l- piperidinyl)carbonyl]-3-pyπolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and 4-ρhenyl-4-piperidinol, the title compoxmd was obtained in 84 % purity by HPLC. MS(ΕSI+): m/z = 534.
Example 327: (2S,4EZ)-l-(rLl'-biphenyl1-4-ylcarbonylVN-r(lS.2S)-2-hvdroxycyclohexyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and (lS,2S)-2-aminocyclohexanol, the title compound was obtained in 84 % purity by HPLC. MS(ΕSI+): m/z = 436.
Example 328: (2S-4EZ)-l-(r l'-biphenyl1-4-ylsulfonylVN-r(lS.2S)-2-hvdroχycvclohexyll-4- (methoxyimino -2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl]-4-sulfonyl chloride, and (lS,2S)-2-aminocyclohexanol, the title compound was obtained in 61 % purity by HPLC. MS(ΕSI+): m/z = 472. Example 329: (2S,4EZ)-N-benzyl-l-([l J'-biphenyl]-4-ylcarbonvD-N-(2-hvdroxyethyl -4- (methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and 2-(benzylamino)ethanol, the title compoxmd was obtained in 74% purity by HPLC. MS(ΕSI+): m/z = 472.
Example 330: (2S.4EZ)-N-benzyl-N-(2-hvdroxyethyl)-4-(methoxyimino)-l -r4-(3-pyri-dinvD- benzoyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and 2-(benzylamino)ethanol, the title compound was obtained in 82 % purity by HPLC. MS(ESI+): m/z = 473.
Example 331 : (3EZ.5S)-1-([1 J'-biphenvn-4-ylcarbonvn-5-{r(3i?S)-3-hydroxypiperidinyl]- carbonyl) -3-pyπolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (3RS)-3-piperidinol, the title compoxmd was obtained in 78 % purity by HPLC. MS(ΕSI+): m/z = 422.
Example 332 : (3EZ5S1-5- l[(3igS)-3-hvdroxypiperidinyl1carbonyl) - 1 -r4-(4-pyridinyl - benzoyl] -3 -pyπolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(4-pyridinyl)berιzoic acid, and (3RS)-3-piperidinol, the title compoxmd was obtained in 91 % purity by HPLC. MS(ΕSI+): m/z = 423. Example 333: (3EZ.5S)-5-j[(3RS)-3-hvdroxypiperidinyl]carbonyl)-l-r4-(3-ρyridinvn- benzoyl]-3-pyrrolidmone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)be_izoic acid, and (3i_S)-3-piperidinol, the title compoxmd was obtained in 84 % purity by HPLC. MS(ΕSI+): m/z = 423.
Example 334: (3EZ.5SH -([1.1 '-biphenyll-4-ylsulfonyl -5- {r(3RS)-3-hydroxypiperidinyl]- carbonyl) -3-pyπolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (3RS)-3-piperidinol, the title compoxmd was obtained in 79 % purity by HPLC. MS(ESI+): m/z = 458.
Example 335: (2S.4EZ)-l-(ri.r-biphenvn-4-ylcarbonylVN-r(lS.2S)-2-hvdroxy-l- (hvdroxymethyl)-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and (lS,2S)-2-amino-l-phenyl-l,3-propanediol, the title compoxmd was obtained in 88 % purity by HPLC. MS(ΕSI+): m/z = 488.
Example 336: (2S.4EZ)-N-r(lS.2S -2-hvdroxy-l-(hvdroxymethylV2-phenylethyl]-4- (methox vimino)- 1 - f4-(4-p yridinvDbenzo yl] -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and (lS,2S)-2-amino-l-phenyl-l,3-propanediol, the title compound was obtained in 64 % purity by HPLC. MS(ΕSI+): m z = 489. Example 337: (2S-4EZ)-N-r(lS.2S -2-hydroxy-l-(hvdroxymethyl)-2-phenylethvn-4- (methoxyimino)-l-[4-(3-pyridinyπbenzoyl1-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (lS,2S)-2-amino-l -phenyl-1 ,3-propanediol, the title compound was obtained in 93 % purity by HPLC. MS(ΕSI+): m/z = 489.
Example 338: (2S.4EZ.-1 -(H .1 '-biphenyl]-4-ylsulfonylVN-r(lS.2S -2-hvdroxy-l - (hvdroxymethyl)-2-phenylethyl1-4-(methoxyimmo)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (lS,2S)-2-amino-l -phenyl- 1,3-propanediol, the title compoxmd was obtained in 82 % purity by HPLC. MS(ΕSI+): m/z = 524.
Example 339: (2S.4EZ)-N-(2-anilinoethvn- 1 -(\ 1.1 '-biρhenyl]-4-ylcarbonviy4-(methoχy- imino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and N1 -phenyl- 1,2-ethanediamine, the title compound was obtained in 93 % purity by HPLC. MS(ESI+): m/z = 457.
Example 340: (2S,4EZ)-N-(2-amlinoethyl)-4-(methoxyimino)- 1 -[4-(4-pyridinyl benzoyl]-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and N1 -phenyl- 1,2-ethanediamine, the title compoxmd was obtained in 85 % purity by HPLC. MS(ΕSI+): m/z = 458. Example 341 : (2S.4EZ)-N-(2-anilinoethvn-4-(methoxyimmoVl-r4-(3-pyridinyl)benzoyl]-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and N1 -phenyl- 1,2-ethanediamine, the title compound was obtained in 85 % purity by HPLC. MS(ΕSI+): m/z = 458.
Example 342: (2S.4EZ)-N-(2-anilinoethyl')-4-(methoxyiminoVl -r4-(2-pyridinyl)bei_zoyl]-2- pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 4-(2-pyridinyl)benzoic acid, and N1 -phenyl- 1,2-ethanediamine, the title compoxmd was obtained in 67 % purity by HPLC. MS(ESI+): m/z = 458.
Example 343 : (2S.4EZ -N-(2-anilinoethylV 1 -(] 1 ,1 '-biphenvn-4-ylsulfonyl)-4-(methoxy- imino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-ρyπolidinecarboxylic acid, [1 ,1 '-biphenyl] -4-sulfonyl chloride, and N1 -phenyl- 1,2-ethanediamine, the title compound was obtained in 73 % purity by HPLC. MS(ΕSI+): m/z = 493.
Example 344: (3EZ.5S)-l-(r l'-biρhenyl]-4-ylcarbonylV5-r(4-hydroxy-l-piperidinyl)- carbonyl] -3 -p yπolidinone O-methyloxime
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1 ,1 '-biphenyl] -4-carbonyl chloride, and 4-piperidinol, the title compoxmd was obtained in 86 % purity by HPLC. MS(ΕSI+): m/z = 422. Example 345 : (3EZ,5S)-1 -(f 1.1 '-biphenyl]-4-ylsulfonylV5-r(4-hvdroxy-l -piperidinyl - carbonyl]-3-pyrrolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-sulfonyl chloride, and 4-piperidinol, the title compoxmd was obtained in 68 % purity by HPLC. MS(ΕSI+): m/z = 458.
Example 346: (2S,4EZ)-N-r(lS.2R.3S.4R -3-(aminocarbonyl bicvclor2.2.nhept-5-en-2-yl]-l- ([1,1 '-biphenvn-4-ylsulfonyl)-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (l-R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 79 % purity by HPLC. MS(ESI+): m/z = 509.
Example 347: (2S.4EZ)-N-(3-amino-3-oxopropylVl-(ri.l'-biphenyl]-4-ylcarbonvD-4- (methoxyimino)-2-ρvπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-ρyπolidinecarboxyUc acid, [1,1 '-biphenyl] -4-carbonyl chloride, and 3-aminopropanamide, the title compound was obtained in 71 % purity by HPLC. MS(ESI+): m/z = 409.
Example 348: (2S.4EZ)-N-r(lS.2S.3R.4R)-3-(aminocarbonyl)bicvclor2.2.1]hept-5-ep-2-yl]-l- ([1.1 '-biphenyl]-4-ylsulfonyl -4-(methoxyimino -2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and (li?,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 83 % purity by HPLC. MS(ESI+): m/z = 509. Example 349: (2SAEZ)- \l .l'-biphenyl]-4-ylcarbonyl)-N-(4-hvdroxybutyl -4-(methoxy- imino)-2-pyπoli dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and 4-amino-l -butanol, the title compoxmd was obtained in 68 % purity by HPLC. MS(ΕSI+): m/z = 410.
Example 350: (2S,4EZ)-l-(ri.r-biphenyl]-4-ylsulfonylVN-(4-hvdroxybutyl -4-(methoxy- imino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-sulfonyl chloride, and 4-amino-l -butanol, the title compound was obtained in 78 % purity by HPLC. MS(ΕSI+): m/z = 446.
Example 351: (2S.4EZ)-l-( lJ'-biphenyl]-4-ylsulfonylVN-[(lR.2RV2-(hvdroxymethyl - cvclohexyl]-4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [l,l'-biphenyl]-4-sulfonyl chloride, and [(lR,2R)-2-aminocyclohexyl]methanol, the title compoxmd was obtained in 40 % purity by HPLC. MS(ΕSI+): m/z = 486.
Example 352: (2S,4EZ)-l-([ l'-biphenyl1-4-ylsulfonyl)-N-r(li?.2S.3R.4S)-3-(hydroxy- methyl)bicvclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(ter/- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidmecarboxylic acid, [1,1 '-biphenyl]-4-sulfonyl chloride, and [(lS,2i-,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title compoxmd was obtained in 58 % purity by HPLC. MS(ΕSI+): m/z = 498. Example 353: (2S.4EZ -l-([l '-biphenyl]-4-ylsulfonyl -N-r(lR.2S)-2-(hvdroxymethyl - cvcloheχyl1-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [l,l'-biphenyl]-4-sulfonyl chloride, and [(lS,2R)-2-aminocyclohexyl]methanol, the title compoxmd was obtained in 41 % purity by HPLC. MS(ΕSI+): m/z = 486.
Example 354: (2S.4E and 4Z)-N-[(2RS)-2-hvdroχy-2-ρhenylethyl]-4-(methoxyiminoVl-r(2'- methvir 1.1 '-biphenyl] -4-yl)carbonyl] -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-ρyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carbpxylic acid, and (li?S)-2 -amino- 1 -phenylethanol, the title compounds were obtained as a mixture of Ε/Z-isomers of the oxime functionality. Separation of the isomers by flash chromatography yielded (2S,4E)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l - [(2'-methyl[l, -biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide in 98.9 % purity and (2S,4Z)-N-[(2RS)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biρhenyl]- 4-yl)carbonyl]-2-pyrrolidinecarboxamide in 99.9% purity by HPLC. MS(ΕSI+): m/z = 472.
Example 355: (2S.4E and 4Z)-N-[(2S)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimmoVl-r(2'- methyir 1 , 1 '-biphenyl]-4-yl carbonyl]-2-p wolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and (lS)-2-amino-l -phenylethanol, the title compounds were obtained as a mixture of Ε/Z-isomers of the oxime functionality. Separation of the isomers by flash chromatography yielded (2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'- methyl[l, -biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide in 98.9 % purity and (2S,4Z)- N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]-4- yl)carbonyl]-2-ρyπolidinecarboxamide in 99.8 % purity by HPLC. MS(ΕSI+): m/z = 472. Example 356: (2S.4E and 4Z)-N-r(2RV2-hvdroχy-2-phenylethyl]-4-(methoxyimino -l-[(2'- methyl[ 1 , 1 '-biphenyl]-4-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[ 1 , 1 '-biphenyl]-4- carboxylic acid, and (lR)-2-ammo-l-phenylethanol, the title compoxmds were obtained as a mixture of Ε/Z-isomers of the oxime functionality. Separation of the isomers by flash chromatography yielded (2S,4_5 -N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l -[(2'- methyl[l,l'-biphenyl]-4-yl)carbonyl]-2-ρyπolidmecarboxamide in 99.7 % purity and (2S,4Z)- N-[(2R)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)- 1 -[(2'-methyl[ 1 , 1 '-biphenyl] -4- yl)carbonyl]-2-ρyπolidinecarboxamide in 99.7 % purity by HPLC. MS(ΕSI+): m/z = 472.
Example 357: (2S.4EZ)-l-(ri.r-biphenyl]-4-ylcarbonvn-N-r(lR.2S)-2-(hvdroxymethyl)- cvclohexyl1-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-ρyπolidinecarboxylic acid, [l,l'-biphenyl] -4-carbonyl chloride, and [(lS,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 63 % purity by HPLC. MS(ΕSI+): m/z = 450.
Example 358: (2SAEZ)- 1 -(f 1.1 '-biphenyl]-4-ylcarbonyl)-N-r2-hvdroxy- 1 -(hvdroxymethylV ethyl]-4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and 2-amino-l,3-propanediol, the title compoxmd was obtained in 61% purity by HPLC. MS(ESI+): m/z = 412.
Example 359: (2S.4EZ)-N-r(lS.2R.3S.4R -3-(aminocarbonvnbicvclor2.2.nhept-5-en-2-vn-l- ([l. -biphenyl]-4-ylcarbonylV4-(methoxyimino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and (li-,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 68 % purity by HPLC. MS(ESI+): m/z = 473.
Example 360: (2S.4EZ)-N-r(lS.2S,3i?,4R -3-(aminocarbonvnbicvclor2.2.11hept-5-en-2-yl]-l- ([l.r-biphenyl1-4-ylcarbonyl -4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [ 1 , 1 '-biphenyl]-4-carbonyl chloride, and (lR,2i-,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 78 % purity by HPLC. MS(ΕSI+): m/z = 473.
Example 361 : (2S.4EZ)-l-(ri.r-biphenvn-4-ylcarbonyl -N-r(2S)-2-hvdroxy-2-phenyl-ethvn- 4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (lS)-2-amino-l-phenylethanol, the title compoxmd was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 458.
Example 362: (2RS)-3-((r(2S.4EZ)-l-(ri.l'-biphenvn-4-ylcarbonylV4-(methoxyiminoV pyπolidinyl] carbonyl) amino)-2-hydroxypropanoic acid
Following the general method as outlined in Example 22, starting from (2S,4EZ)-ϊ-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and (2RS)-3-amino-2-hydroxypropanoic acid, the title compoxmd was obtained in 44 % purity by HPLC. MS(ΕSI+): m/z = 426.
Example 363 : (2SAEZ)-N-\( li?.2S)-2-(ammocarbonyl)c vclohexyl]- 1 -([ 1.1 '-biphenyl]-4- ylcarbonyl -4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [ 1 , 1 '-biphenyl] -4-carbonyl chloride, and (lS,2R)-2-aminocyclohexanecarboxamide, the title compoxmd was obtained in 89 % purity by HPLC. MS(ESI+): m/z = 463.
Example 364: (2S.4EZ)-l-(ri.r-biphenyl]-4-ylcarbonyl)-N-r(li?S)-2-hvdroχy-l-methyl-ethyl]- 4-(methoχyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and (2RS)-2-amino-l-propanol, the title compoxmd was obtained in 81 % purity by HPLC. MS(ΕSI+): m/z = 396.
Example 365: (2S.4EZ)-l-(rLr-biphenyl]-4-ylcarbonylVN-[(lS.2S)-2-hvdroxy-l- (hvdroxymemyl)-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (lS,2S)-2-amino-l -(4-nitrophenyl)- 1, 3 -propanediol, the title compound was obtained in 70 % purity by HPLC. MS(ESI+): m/z = 533.
Example 366 : 4-( { K2SAEZ)- 1 ~(\ 1.1 '-biphenyl] -4-ylcarbonylV 4-(methoxyimino)pyrro- lidinyl] carbonyl) aminoϊbutanoic acid
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and 4-aminobutanoic acid, the title compoxmd was obtained in 57 % purity by HPLC. MS(ΕSI+): m/z = 424.
Example 367: (2S,4EZ)-N-r(2S)-2-hvdroxy-2-phenylethyl]- 1 -r(2'-methoxyr 1.1 '-biphenyll-4- yl)carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1 , 1 -biphenyl]- 4-carboxylic acid, and (15)-2-amino-l -phenylethanol, the title compound was obtained in 90 % purity by HPLC. MS(ESI+): m/z = 488.
Example 368: (2S.4EZ)-N-r(2RS)-2-hvdroxy-2-(2-naphthyl ethyl]-l-[(2'-methoχy l.l'- biphenyl] -4-yl)carbonyl] -4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1 , 1 '-biphenyl]- 4-carboxylic acid, and (lRS)-2-amino-l-(2-naphthyl)ethanol, the title compound was obtained in 67 % purity by HPLC. MS(ΕSI+): m/z = 538.
Example 369: (2S.4EZ)-N-r(li?S)-2-hvdroxy-l-methylethyl]-4-(methoxyimino -l-r(2'- methyl[ 1 , 1 '-biphenyl]-4-yl carbonyl]-2-p yπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and (2RS)-2-amino-l-propanol, the title compoxmd was obtained in 88 % purity by HPLC. MS(ΕSI+): m/z = 410.
Example 370: (2S.4EZ)-N-[(lS.2S -2-hvdroxy-l-(hvdroxymethylV2-(4-nitrophenyl ethyl]-4- (methoxyimino)- 1 -[(2'-methyl[ 1 , 1 '-biphenyl] -4-yl carbonyl] -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[ 1 , 1 '-biphenyl]-4- carboxylic acid, and (lS,2S)-2-amino-l-(4-nitrophenyl)-l,3-propanediol, the title compoxmd was obtained in 74 % purity by HPLC. MS(ESI+): m/z = 547.
Example 371 : (2S.4EZ)-N-r(lS.2S)-2-hvdroxy-l-(hydroxymethylV2-(4-nitrophenvnethyl]-4- (methoxyiminoV 1 -[(2'-methoχy[ 1 , 1 '-biphenyl]-4-yl carbonyl] -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1 , 1 '-biphenyl]- 4-carboxylic acid, and (lS,2S)-2-ammo-l-(4-nitrophenyl)-l,3-propanediol, the title compoxmd was obtained in 61% purity by HPLC. MS(ESI+): m/z = 563.
Example 372: (3EZ.5S)-5-r(4-hvdroχy-l -piρeridinyl carbonyl1-l -f(2'-methyl[ 1.1 '-biphenyl] -4- vDcarbonyl] -3 -pyrrolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[ 1 , 1 '-biphenyl]-4- carboxylic acid, and 4-piperidinol, the title compoxmd was obtained in 86 % purity by HPLC. MS(ΕSI+): m/z = 436.
Example 373: (2S.4EZ)-N-r(lS.2S3R.4R)-3-(aminocarbonvnbicvclor2.2.1]hept-5-en-2-yl]-4- (methoxyimino - 1 -r(2'-methyl[ 1.1 '-biphenyl] -4-vDcarbonyl] -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l ,l'-biphenyl]-4- carboxylic acid, and (lR,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 55 % purity by HPLC. MS(ΕSI+): m/z = 487.
Example 374: (2S.4EZ)-N-[(2i?S)-2-hydroxy-2-phenylethyl]-l-r(2'-methoxyπ.l'-biρhenyl1-4- yl carbonyl]-4-(methoxyimmo -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1,1 '-biphenyl] - 4-carboxylic acid, and (li?S)-2-amino-l -phenylethanol, the title compoxmd was obtained in 82 % purity by HPLC. MS(ΕSI+): m/z = 488.
Example 375: (2S.4EZ)-N-r(2RS)-2-hydroxypropyl]-4-(methoxyimino)-l -[(2'-methyir 1.1'- biphenyl] -4- vDcarbonyl] -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidmecarboxylic acid, 2'-methyl[ 1 , 1 '-biphenyl]-4- carboxylic acid, and (2RS)-l-amino-2-propanol, the title compound was obtained in 90 % purity by HPLC. MS(ESI+): m/z = 410.
Example 376: (2S.4EZ)-N-r(2RS)-2.3-dihydroxypropyl]-4-(methoxyimino -l-[(2'-methyl- [l '-biphenyl]-4~yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and (2RS)-3 -amino- 1,2-propanediol, the title compoxmd was obtained in 67 % purity by HPLC. MS(ΕSI+): m/z = 426.
Example 377: (2S.4EZ)-N-(3-hvdroxypropyl)-4-(methoxyimino -l-r(2'-methvin.l'-biphenyl]- 4-yl carbonyl]-2-ρvπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l~(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[ 1 , 1 '-biphenyl] -4- carboxylic acid, and 3-amino-l-propanol, the title compound was obtained in 90 % purity by HPLC. MS(ΕSI+): m/z = 410.
Example 378: (2S.4EZ)-N-(2-amino-2-oxoethvD-l-(riJ'-biphenyll-4-ylcarbonylV4- (methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and 2-aminoacetamide, the title compoxmd was obtained in 82 % purity by HPLC. MS(ΕSI+): m/z = 395.
Example 379: (2S,4EZ)-N-(2-ammo-2-oxoethyl -4-(methoxyimino 1 -r(2'-methvir 1.1'- biphenyl -4-yl)carbonyl]-2-pyπoli dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and 2-aminoacetamide, the title compoxmd was obtained in 92 % purity by HPLC. MS(ESI+): m/z = 409.
Example 380: (2S.4EZ)-l-(ri.r-biρhenyl]-4-ylcarbonyl -N-r(2RS)-2-hvdroxy-2-(3- hydroxyphenyl)ethyl]-4-(methoxyimino -2-pyrrolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and 3-[(lR_S)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 88 % purity by HPLC. MS(ΕSI+): m/z = 504.
Example 381: (2S.4EZ)-l-(ri.r-biphenyl1-4-ylcarbonyl)-N-r(lS.2R.3S.4R -3-(hvdroxy- methypbic yclo [2.2.1 ]hept-2-yl] -4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and [(li?,2S,3i-,4S)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title compoxmd was obtained in 64 % purity by HPLC. MS(ΕSI+): m/z = 462.
Example 382: (2S,4EZ)-N-r(lR.2S.3R.4S)-3-(hydroxymethvnbicvclor2.2.11hept-2-yl1-l-r(2'- methoxy[l, -biphenyl]-4-yl carbonyl]-4-(methoxyimino)-2-pyπoli dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1 , 1 '-biphenyl]- 4-carboxylic acid, and [(lS,2R,3S,4R)-3-aminobicyclo[2.2.1]hept-2-yl]methanol, the title compoxmd was obtained in 56 % purity by HPLC. MS(ΕSI+): m/z = 492.
Example 383: (2S.4EZ)-N-(trøn5-4-hvdroxycyclohexyl -l-r(2'-methoxyπ,r-biphenvn-4- yl)carbonyl]-4-(methoxyimino -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1 , 1 '-biphenyl]- 4-carboxylic acid, and trøns-4-aminocyclohexanol, the title compoxmd was obtained in 61 % purity by HPLC. MS(ESI+): m/z = 466.
Example 384: (2S.4EZ)-N-r(lR.2RV2-(hydroχymethvncvclohexyl]-l-[(2'-methoxyri.r- biphenyl] -4-yl)carbonyl] -4-(methoxyimino -2-pyrrolidmecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1 , 1 '-biphenyl]- 4-carboxylic acid, and [(lR,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 68 % purity by HPLC. MS(ΕSI+): m/z = 480.
Example 385: (2S.4EZ^-N-r(2RS)-2-hvdroχy-3-ρhenoχypropyl]-4-(methoχyimino -l-r(2'- methyl[ 1 , 1 '-biphenyl] -4-yl carbonvπ -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and (2RS)-l-amino-3-ρhenoxy-2-ρropanol, the title compoxmd was obtained in 80 % purity by HPLC. MS(ΕSI+): m/z = 502.
Example 386: (2S.4EZ)-N-r(2RS)-2-hydroxy-2-(4-hvdroxyphenvnethyl1-4-(methoχy-imino)- l-[(2'-methyiri,r-biphenyl1-4-yl)carbonyl]-2-ρvπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-ρyπolidinecafboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and 4-[(lRS)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 76 % purity by HPLC. MS(ΕSI+): m/z = 488.
Example 387: (2S.4EZ)-N-r(2RS)-2-hydroχy-2-(4-hydroxyphenyl ethyl]-4-(methoxy-imino)- 1 -[(2 '-methoxy [ 1 , 1 '-biρhenyl]-4-yl)carbonyl]-2-p vπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1 , 1 '-biphenyl]- 4-carboxylic acid, and 4-[(li?S)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 90 % purity by HPLC. MS(ESI+): m/z = 504.
Example 388: (2S,4EZ)-N- (2^S -2-hvdroχy-2-(4-hvdroxy-3-methoxyphenvnethyl]-l-r(2'- methyl[l,r-biphenyl1-4-yl carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[ 1 , 1 '-biphenyl] -4- carboxylic acid, and 4-[(li?S)-2-amino-l-hydroxyethyl]-2-methoxyphenol, the title compoxmd was obtained in 67 % purity by HPLC. MS(ESI+): m/z = 518.
Example 389: (2S.4EZ)-N-r(2RS)-2-hydroxy-2-(4-hvdroxy-3-methoxyρhenvnethyl1- 1 -IY2'- methoxyf 1 , 1 '-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methoxy[ 1 , 1 '-biphenyl]- 4-carboxylic acid, and 4-[(lRS)-2-amino-l-hydroxyethyl]-2-methoxyphenol, the title compound was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 534.
Example 390: (2S.4EZ -N-r(2RS)-2-(3.4-dihydroxyphenylV2-hvdroxyethyll-l-r(2'- methoxy[ 1 , 1 '-biphenyl] -4-yl)carbonyl]-4-(methoχyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methoxy [ 1 , 1 '-biphenyl] - 4-carboxylic acid, and 4-[(lRS)-2-amino-l-hydroxyethyl]-l,2-benzenediol, the title compoxmd was obtained in 69 % purity by HPLC. MS(ΕSI+): m/z = 520.
Example 391: (2R.4EZ)-l-(riJ'-biphenvn-4-ylcarbonvn-N-[(2i?S)-2-hydroxy-2-phenyl- ethyl]-4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2R,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (li?S)-2-amino-l-phenylethanol, the title compound was obtained in 90 % purity by HPLC. MS(ESI+): m/z = 456.
Example 392: (2R.4EZ)-N-r(2RS)-2-hvdroxy-2-phenylethyl1-4-(methoχyiminoVl-r(2'- methyl[ 1 , 1 '-biphenyl] -4-yl carbonyl] -2-p vπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2R,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and (li_S)-2-amino-l-phenylethanol, the title compound was obtained in 94 % purity by HPLC. MS(ΕSI+): m/z = 472.
Example 393: (2S.4EZ)-l-r(2'-cvanori.r-biphenyl1-4-yl carbonyl]-N-f(2RS)-2-hvdroχy-2- phenylethyl]-4-(methoxyimino)-2-pyπoli dinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-cyano[l ,1 '-biphenyl] -4- carboxylic acid, and (lRS)-2-amino-l-phenylethanol, the title compoxmd was obtained in 86 % purity by HPLC. MS(ΕSI+): m/z = 483.
Example 394: (2S.4EZ)-l-r(3'.4'-dichloro l.r-biphenyl]-4-yl carbonvn-N-r(2RS)-2-hvdroxy- 2-ρhenylethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 3 ' ,4' -dichlorofl , 1 '- biphenyl]-4-carboxylic acid, and (li?S)-2-amino-l -phenylethanol, the title compoxmd was obtained in 89 % purity by HPLC. MS(ΕSI+): m/z = 527.
Example 395: (2S.4EZ)-l-r(2'.6'-dimethviri.l,-biphenyn-4-vncarbonyl]-N-[(2RS)-2-hvdroxy- 2-phenylethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',6'-dimethyl[l,l'- biphenyl]-4-carboxylic acid, and (li-S)-2-amino-l -phenylethanol, the title compoxmd was obtained in 95 % purity by HPLC. MS(ESI+): m/z = 486.
Example 396: (2S,4EZ)-l-r(2',3-dimethyllT .1 '-biphenyn-4-yl)carbonyl]-N-r(2i-S)-2-hydroxy- 2-phenylethyl]-4-(methoχyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2' ,3 -dimethyl[l , 1 '- biphenyl] -4-carboxylic acid, and (lRS)-2-amino-l -phenylethanol, the title compoxmd was obtained in 83 % purity by HPLC. MS(ΕSI+): m/z = 486.
Example 397: (2S,4EZ)-N-r(2RS -2-hydroxy-2-(3-hvdroχyphenyl ethyl1-4-(methoxy-imino - l-[(2'-methyl[l '-biphenyl]-4-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biρhenyl]-4- carboxylic acid, and 3-[(li?S)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 70 % purity by HPLC. MS(ΕSI+): m/z = 488.
Example 398: (2S.4EZ)-N-r(2RS)-2-hvdroxy-2-(3-hvdroxyρhenvnethyll-4-(methoxy-imino)- 1 -|"(2'-c yano [1,1 '-biphenyl] -4-yl carbonyl] -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-cyano[l,l'-biphenyl]-4- carboxylic acid, and 3-[(l-flS)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 86 % purity by HPLC. MS(ΕSI+): m/z = 499.
Example 399: (2S,4EZ)-N-r(2RS)-2-hvdroxy-2-(3-hvdroxyphenvnethyl]-4-(methoxy-imino - 1 - [(3 ' ,4 ' -dichlorof 1 , 1 '-biphenyl] -4-yl carbonyl1 -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 3 ' ,4 ' -dichloro [1,1'- biphenyl]-4-carboxylic acid, and 3-[(lRS)-2-amino-l-hydroxyethyl]phenol, the title compound was obtained in 91 % purity by HPLC. MS(ESI+): m/z = 543.
Example 400: (2S,4EZ)-N-r(2RS)-2-hydroxy-2-(3-hvdroxyphenynethyll-4-(methoxy-imino - l-[(2',6'-dimethyl[l,r-biphenyl1-4-yl)carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2 ' ,6 ' -dimethyl [1,1'- biphenyl]-4-carboxylic acid, and 3-[(l_RS)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 502.
Example 401 : (2S.4EZ)-N-r(2RS -2-hvdroxy-2-(3-hvdroxyphenyl)ethvn-4-(methoxy-imino')- l-[(2',3-dimethyl[l,l'-biphenvn-4-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2' ,3 -dimethyl[ 1 , 1 '- biphenyl]-4-carboxylic acid, and 3-[(lRS)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 91 % purity by HPLC. MS(ΕSI+): m/z = 502.
Example 402: (2SAEZ)-l-ϊ(3 4,-dichlow l .1 ,-biphenyl1-4-yl)carbonvn-N-[(2RS)-2-hvdroxy- 2-(4-hydroxyphenyl ethvn-4-(methoxyimmo)-2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 3 ' ,4 ' -dichloro [1,1'- biphenyl]-4-carboxylic acid, and 4-[(li?S)-2-amino-l-hydroxyethyl]phenol, the title compoxmd was obtained in 86 % purity by HPLC. MS(ΕSI+): m/z = 543.
Example 403: (2S.4EZ)-l-r(2',6'-dimethyiri.l'-biphenvn-4-yl carbonyl1-N- (2RS)-2-hvdroxy- 2-(4-hvdroxyphenyl ethyl1-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',6'-dimethyl[l,l'- biphenyl]-4-carboxylic acid, and 4-[(lRS)-2-amino-l-hydroxyethyl]phenol, the title compound was obtained in 89 % purity by HPLC. MS(ESI+): m/z = 502.
Example 404: (2S.4EZ)-! -\(2 3 -dimethyl [1.1 '-biphenyl] -4-yncarbonyl]-N- (2RS)-2-hydroxy- 2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxy imino)-2-pyπolidinecarboxylic acid, 2 ' ,3 -dimethylf 1 , 1 '- biphenyl] -4-carboxylic acid, and 4-[(li?S)-2-amino-l-hydroxyethyl]phenol, the title compound was obtained in 90 % purity by HPLC. MS(ESI+): m/z = 502.
Example 405: (2S.4EZ -l-r(2'.6'-dimethviri.l'-biρhenyl]-4-yl carbonyl]-N-r(2RS)-2-hvdroxy- 3-(4-methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2 ' ,6 ' -dimethyl[ 1 , 1 '- biphenyl]-4-carboxylic acid, and (2i?S)-l-amino-3-(4-methoxyphenoxy)-2-propanol, the title compoxmd was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 546.
Example 406: (2S.4EZ)-l-r(2'.3-dimethyiri,l'-biphenvn-4-yl carbonyl]-N-r(2RS)-2-hvdroxy- 3-(4-methoxyphenoxy propyl]-4-(methoxyimino -2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',3-dimethyl[l ,1 '- biphenyl]-4-carboxylic acid, and (2RS)-l-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound was obtained in 77 % purity by HPLC. MS(ΕSI+): m/z = 546.
Example 407: (2S,4EZ)-N-(2-amino-2-oxoethyl)- 1 -r(2'.6'-dimethvir 1.1 '-biphenyl - yl carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2 ' ,6 ' -dimethyl [1,1 - biphenyl]-4-carboxylic acid, and 2-aminoacetamide, the title compoxmd was obtained in 88 % purity by HPLC. MS(ESI+): m/z = 423.
Example 408 : (2S.4EZ)-N-(2-amino-2-oxoethyl -l -[(2',3-dimethvir 1.r-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',3-dimethyl[l ,1'- biphenyl] -4-carboxylic acid, and 2-aminoacetamide, the title compound was obtained in 85 % purity by HPLC. MS(ΕSI+): m/z = 423.
Example 409: (2S.4EZ)-N-(3-amino-3-oxopropylVl -r(2',6'-dimethvir 1.1 '-biphenyl] -4- yl carbonyl]-4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',6'-dimethyl[l,l'- biphenyl]-4-carboxylic acid, and 3-aminopropionamide, the title compound was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 437.
Example 410: (2S.4EZ)-N-(3-amino-3-oxoρropyl -l-r(2'.3-dimethviπ,l'-biphenyl1-4- yl carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert~ butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',3-dimethyl[l , 1 '- biphenyl]-4-carboxylic acid, and 3-aminopropionamide, the title compoxmd was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 437.
Example 411: (2S.4EZ)-l-r(2'.6'-dimethvin.l'-biphenyl1-4-vncarbonyn-N-r2-hvdroxy-l- (hvdroχymethyl ethyl1-4-(methoχyimmo -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimmo)~2-pyπolidinecarboxylic acid, 2 ' ,6 ' -dimethyl [1,1 - biphenyl] -4-carboxylic acid, and 2-amino-l,3-propanediol, the title compoxmd was obtained in 70 % purity by HPLC. MS(ESI+): m/z = 440.
Example 412: (2S,4EZl-l-r(2',3-dimethyiri.l'-biphenyl]-4-yl)carbonyl]-N-r2-hvdroxy-l- (hydroxymethyl)ethyl]-4-(methoxyimino -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',3-dimethyl[l,l '- biphenyl] -4-carboxylic acid, and 2-amino-l,3-propanediol, the title compound was obtained in 68 % purity by HPLC. MS(ΕSI+): m/z = 440.
Example 413: (2S,4EZ)-l-r(2'-cyanori.l'-biphenyl]-4-yl carbonyl]-N-r(lR.2RV2- (hydroxymethyl cvclohexyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2 ' -cyano [1,1 '-biphenyl] -4- carboxylic acid, and [(lR,2R)-2-aminocyclohexyl]methanol, the title compoxmd was obtained in 78 % purity by HPLC. MS(ΕSI+): m/z = 475.
Example 414: (3EZ.5S -5-(3.4-dihvdro-2(lH)-isoquinolinylcarbonylVl-r(2'.3-dimethviri,r- biphenyl] -4- vDcarbonyl] -3 -p yπolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',3-dimethyl[l,l'- biphenyl]-4-carboxylic acid, and 1,2,3,4-tetrahydroisoquinoline, the title compoxmd was obtained in 77 % purity by ΗPLC. MS(ΕSI+): m/z = 482.
Example 415: (2S.4EZ)-N-r(lRV2-hvdroχy-l-phenylethvn-4-(methoxyiminoVl-r(2'- methyl[ 1 , 1 '-biphenyl] -4-yl carbonyl] -2-p yπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,r-biphenyl]-4- carboxylic acid, and (2R)-2-amino-2-phenylethanol, the title compoxmd was obtained in 91 % purity by HPLC. MS(ESI+): m/z = 472.
Example 416: (2S.4EZ)-l-r(2'.6'-dimethviri.r-biphenyl1-4-yncarbonyl]-N-r2-(4- hvdroxyphenyl)ethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',6'-dimethyl[l,l'- biphenyl] -4-carboxylic acid, and 4-(2-aminoethyl)phenol, the title compoxmd was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 486.
Example 417: (2S.4EZ)-l-r(2'.3-dimethyiriJ'-biphenyl1-4-yl)carbonvn-N-r2-(4-hvdroxy- phenyl)ethyl1-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxy carbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2 ' ,3 -dimethyl [1,1 - biphenyl] -4-carboxylic acid, and 4-(2-aminoethyl)phenol, the title compoxmd was obtained in 83 % purity by HPLC. MS(ΕSI+): m/z = 486.
Example 418: (2SAEZ)-l -r(2'.6'-dimethyllT .1 '-biphenyl]-4-vncarbonyl1-N-r2-(3-hvdroxy- phenyl)ethyl1-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',6'-dimethyl[l ,1'- biphenyl]-4-carboxylic acid, and 3-(2-aminoethyl)phenol, the title compoxmd was obtained in 81 % purity by HPLC. MS(ΕSI+): m/z = 486.
Example 419: (2S.4EZ)-l-[(2'.3-dimethyl[l.r-biphenvn-4-vncarbonyl]-N-r2-(3-hvdroxy- phenyl ethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2',3-dimethyl[l,l'- biphenyl]-4-carboxylic acid, and 3-(2-aminoethyl)phenol, the title compound was obtained in 89 % purity by HPLC. MS(ESI+): m/z = 486.
Example 420: (2S.4EZ)-l-r(2'.3-dimethyl[l.r-biphenyll-4-vncarbonvn-N-[(lR.2S)-2- hydroxy-1.2-diρhenylethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxy imino)-2-pyπolidinecarboxylic acid, 2 ' ,3 -dimethyl [1,1'- biphenyl]-4-carboxylic acid, and (lS,2R)-2-amino-l,2-diρhenylethanol, the title compoxmd was obtained in 73 % purity by HPLC. MS(ΕSI+): m/z = 562.
Example 421 : (2RS)-2-r(((2S.4EZ)-4-(methoxyimino)-l-r(2'-methvin,l'-biphenyl]-4- yl carbonyl]pyrrolidinyl) carbonyl amino]-3-phenylpropanoic acid
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbony l)-4-(methoxy imino)-2-pyπolidinecarboxylic acid, 2 ' -methyl[ 1 , 1 '-biphenyl] -4- carboxylic acid, and DL-phenylalanine, the title compound was obtained in 62 % purity by HPLC. MS(ΕSI+): m/z = 500.
Example 422: (2S,4EZ -N-r(li?.2S)-2-(aminocarbonyncvclohexyl]-l-r(2'.6'-dimethviri.l'- biphenyl]-4-yl carbonyl]-4-(methoxyimmoV2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-ρyπolidinecarboxylic acid, 2 ' ,6 ' -dimethyl [1,1'- biphenyl] -4-carboxylic acid, and (lS,2R)-2-aminocyclohexanecarboxamide, the title compoxmd was obtained in 92 % purity by HPLC. MS(ESI+): m/z = 491.
Example 423 : (2S.4EZ -N-[(lR.2S)-2-(aminocarbonvncvclohexyn-l-r(2'.3-dimethviri .1'- biphenyl]-4-yl carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2' ,3 -dimethylfl , 1 '- biphenyl] -4-carboxylic acid, and (lS,2i?)-2-aminocyclohexanecarboxamide, the title compoxmd was obtained in 91 % purity by HPLC. MS(ESI+): m/z = 491.
Example 424: 4'- (iY2S.4EZ)-2- {r4-(2-hydroxyethylV 1 -piperazinyll carbonyl) -4- (methoxyimino p yrrolidinyl] carbonyl) [T , 1 '-biphenyl] -2-carbonitrile
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2 ' -cyano [1,1 '-biphenyl] -4- carboxylic acid, and 2-(l-piperazinyl)ethanol, the title compoxmd was obtained in 89 % purity by HPLC. MS(ΕSI+): m/z = 476.
Example 425: (3EZ.5S)-l-r(3'.4,-dichlorori.l'-biphenyl1-4-yl carbonyl1-5-{r4-(2- hydroxyethyl)-l-piperazinyl1carbonyl)-3-pyπolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 3 ' ,4 ' -dichloro [1,1 - biphenyl] -4-carboxylic acid, and 2-(l-piperazinyl)ethanol, the title compoxmd was obtained in 86 % purity by HPLC. MS(ΕSI+): m/z = 520.
Example 426: (3EZ.5S)-l-r(2',6'-dimethyiri,r-biphenyl1-4-yl carbonyl1-5-(r4-(2- hvdroχyethyl)-l-piperazmyl]carbonyl)-3-ρvπolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2 ',6' -dimethyl [1 ,1'- biphenyl] -4-carboxylic acid, and 2-(l-piperazinyl)ethanol, the title compound was obtained in 79 % purity by HPLC. MS(ΕSI+): m/z = 479.
Example 427: (3EZ.5S)-l-r(2'.3-dimethviri,r-biphenyl1-4-yl)carbonyl]-5-(r4-(2- hydroxyethyiy 1 -piperazinyl]carbonyl) -3 -pyrrolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2 ' ,3 -dimethyl [ 1 , 1 '- biphenyl]-4-ca boxylic acid, and 2-(l-piρerazinyl)ethanol, the title compound was obtained in 86 % purity by HPLC. MS(ESI+): m/z = 479.
Example 428 : (3EZ.5S)-1 -rø'-methyl, 1.1 '-biphenyl]-4-yl)carbonyl]-5-( {444-
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and l-[4-(trifluoromethyl)phenyl]piperazine, the title compoxmd was obtained in 89 % purity by HPLC. MS(ΕSI+): m/z = 565.
Example 429: (3EZ.5S)-l-r(2'-methviri.l'-biphenyl]-4-vncarbonyl1-5-({4-r3-(trifluoro- methypphenyl] - 1 -piperazinyl) carbonyl)-3 -pyπolidinone O-methyloxime
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidmecarboxylic acid, 2 ' -methyl [1,1 '-biphenyl] -4- carboxylic acid, and l-[3-(trifluoromethyl)phenyl]piperazine, the title compoxmd was obtained in 88 % purity by HPLC. MS(ΕSI+): m/z = 565.
Example 430: (2S.4EZ)-4-(methoχyiminoVl-[(2'-methviri.r-biphenyl1-4-vncarbonyl1-2- pVHolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l ,l'-biphenyl]-4- carboxylic acid, and ammonia (0.5M in dioxane), the title compound was obtained in 88 % purity by HPLC. MS(ESI+): m/z = 352.
Example 431: (2S.4EZ)-4-(methoxyimino)-N-methyl-l-r(2'-methviri.r-biphenyl]-4- yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and methylamine (2M in methanol), the title compoxmd was obtained in 96 % purity by HPLC. MS(ESI+): m/z = 366.
Example 432: (2S.4EZ)-4-(methoχyimino -N V-dimethyl-l-r(2'-methyiri.l'-biρhenvn-4- yl)carbonyl1-2 -pyrrolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxy imino)-2-pyπolidinecarboxylic acid, 2 ' -methyl[ 1 , 1 '-biphenyl] -4- carboxylic acid, and dimethylamine (5.6M in ethanol), the title compound was obtained in 94 % purity by HPLC. MS(ΕSI+): m/z = 380.
Example 433: (2S.4EZ -N-r(3R -3-hvdroxy-3-phenylpropyl]-4-(methoxyimino -l-r(2'- methyl[l, -biphenvn-4-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and (lR)-3-amino-l-phenyl-l-propanol, the title compoxmd was obtained in 94% purity by HPLC. MS(ΕSI+): m/z = 486.
Example 434: (2S.4EZ)-N-r(3S)-3-hvdroxy-3-phenylpropyl1-4-(methoxyiminoVl-r(2'- methviπ , 1 '-biphenyl]-4-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- bu toxycarbonyl)-4-(methoxy imino)-2-pyπolidinecarboxylic acid, 2 ' -methyl [ 1 , 1 '-biphenyl] -4- carboxylic acid, and (lS)-3 -amino- 1 -phenyl- 1-propanol, the title compoxmd was obtained in 91 % purity by HPLC. MS(ΕSI+): m/z = 486.
Example 435: (2S,4EZ)-l-([l.r-biphenyl]-4-ylcarbonylVN-r(3J?V3-hvdroxy-3-phenyl- propyl]-4-(methoxyimmo)-2-pwolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimmo)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (li?)-3-amino-l-phenyl-l-propanol, the title compoxmd was obtained in 94 % purity by HPLC. MS(ESI+): m/z = 472.
Example 436: (2S.4EZ)-l-(ri.r-biphenyl]-4-ylcarbonyl)-N-r(3S)-3-hvdroxy-3-phenyl-ρroρyl]- 4-(methoxyimino)-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl] -4-carbonyl chloride, and (lS)-3-amino-l-phenyl-l-propanol, the title compoxmd was obtained in 93 % purity by HPLC. MS(ESI+): m/z = 472.
Example 437: (2S.4EZ)-N-r(2S)-2-hvdroxy-2-phenylethyl]-4-(methoxyimino)-l-fr2'- (trifluoromethyl)[ 1 , 1 '-biphenyl] -4-yl] carbonyl) -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2'-(trifluoromethyl)[ 1,1'- biphenyl] -4-carboxylic acid, and (lS)-2-amino-l -phenylethanol, the title compound was obtained in 87 % purity by HPLC. MS(ΕSI+): m/z = 526.
Example 438: (2S.4EZ)-N-r(2S -2-hvdroxy-2-phenylethyl].-4-(methoxyimino)-l- i\ - chlorof 1 , 1 '-biphenyl]-4-yl]carbonyl) -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-chloro[ 1 , 1 '-biphenyl] -4- carboxylic acid, and (lS)-2-amino-l -phenylethanol, the title compound was obtained in 89% purity by HPLC. MS(ΕSI+): m/z = 492.
Example 439: (2S.4EZ)-N-(2-hvdroxyphenyl -4-(methoχyimino -l-r(2'-methviri.r-biρhenvn- 4-yl carbonyl]-2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2'-methyl[l,l'-biphenyl]-4- carboxylic acid, and 2-aminophenol, the title compound was obtained in 88 % purity by HPLC. MS(ESI+): m/z = 444.
Example 440: (2S,4EZ)-N-[2-(hvdroxymethvnphenyl]-4-(methoxyiminoV 1 - (2'-methyl-r 1.1 '- biphenyl] -4- ypcarbonyl] -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2'-methyl[ 1 , 1 '-biphenyl]-4- carboxylic acid, and (2-aminophenyl)methanol, the title compound was obtained in 86% purity by HPLC. MS(ΕSI+): m/z = 458.
Example 441 : (2S,4EZ)-N-r(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-r(2- methyl[ 1 , 1 '-biphenyn-4-yl carbonyl] -2-pyπolidinecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-\-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2-methyl[ 1 , 1 '-biphenyl]-4- carboxylic acid, and (lS)-2-amino-l-phenylethanol, the title compoxmd was obtained in 95 % purity by HPLC. MS(ΕSI+): m/z = 472.
Example 442: (2SAE and 4Z)-l-([l.l'-biphenyl1-4-ylcarbonyl -N-r(2S)-2-hydroxy-2- phenylethyl]-4-(methoxyimino)-2-pyπolidmecarboxamide
Following the general method as outlined in Example 22, starting from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, [1,1 '-biphenyl]-4-carbonyl chloride, and (lS)-2-amino-l-phenylethanol, the title compoxmds were obtained as a mixture of Ε/Z-isomers of the oxime functionality. Separation of the isomers by flash chromatography yielded (2S,4E)-l-(ri.l'-biphenyl1-4-ylcarbonyl -N-r(2S)-2-hvdroxy-2-phenylethyl]-4- (methoxyimino)-2-pyπolidmecarboxamide in 98.8 % purity and (2S.4Z)- 1 -([ 1 , 1 '-biphenyl]-4- ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino -2-pyπolidinecarboxamide in 97.4 % purity by HPLC. MS(ΕSI+): m/z = 458.
Example 443: (2S.4EZ)-4-(methoxyimino -l-r(2'-methyl[l.r-biphenyl1-4-vncarbonvn-N-(2- phenylethyl)-2-pyπolidinecarboxamide Following the general method as outlined in Example 22, startmg from (2S,4EZ)-l-(tert- butoxycarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxylic acid, 2-methyl[l,l'-biphenyl]-4- carboxylic acid, and 2-phenylethanamine, the title compoxmd was obtained in 89% purity by HPLC. MS(ΕSI+): m/z = 456.
Example 444 : Preparation of a pharmaceutical formulation
The following formulation examples illustrate representative pharmaceutical compositions according to the present invention being not restricted thereto.
Formulation 1 — Tablets
A pyπolidine compound of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ration. A minor amount of magnesium stearate is added as a lubricant. The mixture is foi ed into 240-270 mg tablets (80-90 mg of active pyrrolidine compound per tablet) in a tablet press.
Formulation 2 — Capsules
A pyπolidine compound of formula I is admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active pyπolidine compoxmd per capsule).
Formulation 3 — Liquid
Apyπolidine compound of formula I (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
A pyπolidine compoxmd of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active pyπolidine compoxmd) in a tablet press. Formulation 5 - Injection
A pyrrolidine compound of formula I is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
Example 445 : Biological assays
a) In vitro binding assay (SPA)
Membranes from HEK293EBNA cells expressing the hOT receptor were resuspended in buffer containing 50 mM Tris-HCl, pH 7.4, 5 mM MgC12 and 0.1 % BSA (w/v). The membranes (2-4 μg) were mixed with 0.1 mg wheat-germ aglutinin (WGA) SPA bead (type A) and increasing concentrations of [l^Sη-OVTA (for saturation binding experiments) or 0.2 nM [125π_0VTA (for competition binding experiments). Non specific binding was deter-mined in the presence of 1 μM Oxytocin. The total assay volume was 100 μl. The plates were incubated at room temperature for 30 min and counted on a Mibrobeta plate counter. The competition binding data were analysed using the iterative, nonlinear, curve-fitting program, Prism.
b) Biological Results — Discussion
The binding affinities to the oxytocin receptor of the pyπolidine derivatives claimed in the formula I were assessed using the above described in vitro biological assay. Representative values for some example compoxmds are given in Table 1 below. The values refer to the binding capacity of the example compoxmds accordmg to formula I to the Oxytocin receptor. From the values shown in Table 1 it can be derived that said test compounds according to formula I do show a significant binding to the Oxytocin receptor.
Table 1 Binding affinity
Structure lUPAC-Name human OT-R-
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4
(methoxyιmιno)-1-[(2'-methyl[1,1'-bιphenyl]- 0.13
4-yl)carbonyl]-2-pyrrolιdιnecarboxamιde
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4
(methoxyιmιno)-1-[(2'-methyl[1,1'-bιphenyl]- 0.07
4-yl)carbonyl]-2-pyrrolιdιnecarboxamιde
(3Z,5S)-5-(1 H«benzιmιdazol-2-yl)-1-([1 ,1 '- bιphenyl]-4-ylcarbonyl)-3-pyrrolιdιnone O- 0.63 methyloxime
(2S,4Z)-1-([1,1'-bιphenyl]-4-ylcarbonyl)-4-
(chloromethylene)-N-[(2RS)-2-hydroxy-2- 0.35 phenylethyl]-2-pyrrolιdιnecarboxamιde
(2S.4EZ)-N-[(2RS)-2-hydroxy-2- phenylethyl]-4-(methoxyιmιno)-1-(3- 2.3 phenoxybenzoyl)-2-pyrrolιdιnecarboxamιde
Binding affinity
Structure lUPAC-Name human OT-R
!C50 {μM)
(2S,4EZ)-N-(3-amιno-3-oxopropyl)-1-[(2',3- dιmethyl[1,1'-bιphenyl]-4-yl)carbonyl]-4- 0.54
(methoxyιmιπo)-2-pyrrolιdιnecarboxamιde
(2S,4EZ)-1-[(2,-chlorot1,1'-bιp enyl]-4- yl)carbonyl]-N-[(2S)-2-hydroxy-2- phenylethyl]-4-(nnethoxyιmιno)-2- 0.17 pyrrolidmecarboxamide
(2S,4EZ)-N-(3-hydroxypropyl)-4-
(methoxyiminoM- '-methylfl.l'-bipheriyl]- 0.37
4-yl)carbonyl]-2-pyrrolιdιnecarboxamιde
(3EZ,5S)-5-[(4-hydroxy-1 - pιpeπdιnyl)carbonyl]-1-[(2'-methyl[1,1'- bιp enyl]-4-yl)carbonyl]-3-pyrrolιdιnone O- 0.30 methyloxime
(2S,4EZ)-N-[(1R,2R)-2-
(hydroxymethyl)cyclohexyl]-1-[(2'- met oxy[1 ,1 '-bιphenyl]-4-yl)carbor.yl]-4- 0.55
(met oxyιmιno)-2-pyrrolιdιnecarboxamιde
According to a prefeπed embodiment, the compoxmds display binding affinities (UT, (μM)) of less 0.40 μM, more prefeπed of less than 0.1 μM. c) Functional assay No. 1: Inhibition of Ca2+ -mobilization by FLIPR
Preparing the plates: FLIPR-plates were pre-coated with PLL lOμg/ml + 0.1% gelatine for 30min up to 2 days at 37 °C (for HEK-cells). The cells were plated out into 96-well plates (60000 cells/well).
Labelling with fluo-4: 50μg fluo-4 were dissolved in 20μl pluronic acid (20% in DMSO). The dissolved fluo-4 was then diluted in 10ml DMEM-F12 medium without FCS. The medium was removed from the plates, followed by one wash with DMEM-F12 medium. Now, lOOμl of the DMEM-F12 medium containing fluo-4 were added and the cells incubated for 1-1.5h (CHO-cells), and 1.5-2h (HEK-cells).
Buffer: 145mM NaCl, 5mM KCI, ImM MgCl2, lOmM Hepes, lOmM Glucose, EGTA. Adjust to pH 7.4.
Preparation of agonists and antagonists: A minimum of 80μlΛvell of agonists and anta-gonists (5x) in the above buffer (lx) were prepared (96-well plates).
The activities of the pyπolidine derivatives according to formula I were assessed using the above described in vitro biological assay. Representative values for some example compoxmds are given in Table 2 below. The values refer to the capacity of the example compounds according to formula I to effectively antagonize oxytocin-induced intracellular Ca2+- mobilization mediated by the Oxytocin receptor. From the values shown in Table 2 it can be derived that said example test compoxmds according to formula I do exhibit a significant activity as Oxytocin receptor antagonists.
Table 2
Inhibition ςf Ca .2'*
Structure lUPAG-Name mobilization, JhOT-R
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4
(methoxyimino)-1-[(2'-methyl[1-1'-biphenyl]- 0.07
4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4
(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]- 0.03
4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(3R)-3-hydroxy-3- phenyIpropyi]-4-(meth°χyi 'no)-1-[(2'- methyl[1 ,1 '-biphenyl]-4-yl)carbonyl]-2- 0.32 pyrrolidinecarboxamide
(3Z,5S)-5-(1 H-benzimidazol-2-yl)-1-([1 ,1'- biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O- 0.4 methyloxime
(2S,4Z)-1 -([1,1 '-biphenyl]-4-ylcarbonyl)-N-
(2-hydroxyethyl)-4-(methoxyimino)-2- 0.65 pyrrolidinecarboxamide d) Functional assay No. 2: Inhibition of IP3-Synthesis in HEK/EBNΛ-OTR cells
Stimulation of the cells: HEK EBNA OTR(rat or human) cells were plated out into costar 12- well plates, and equilibrated for 15-24h with [ H]-inositol in medium without inositol supplement, with 1% FCS (0.5ml/well). 4 μCi/ml were used. After this, the medium containing the label was aspirated. Then was added DMEM (without FCS, inositol), 20mM Hepes, lmg ml BSA containing lOmM LiCl (freshly prepared), for 10-15min at 37°C. The agonists and antagonists were added for the time required (15-45min), followed by aspiration of the medium. The reaction was stopped with lml STOP-solution (0.4 M perchloric acid), and let sit for 5-lOmin at RT (not longer). Then, 0.8ml were transfeπed into tubes containing 0.4ml of neutralizing solution (0.72 M KOH/0.6M KHCO3), and the tubes vortexed and kept in the cold at least for 2h. At this stage, samples could be kept over a prolonged period of time.
Separation of IP's: The samples were spun in a table top centrifuge at 3000-4000 rpm for 15min. lml of the supernatant was transfeπed to new tubes containing 2.5ml H O. Packed resin (0.8ml) was equilibrated with 20ml H2O, and the whole samples poured onto the columns. To discard free inositol, two washes with 10ml H2O were carried out.
Elution of total IP's: The elution was achieved using 3ml 1M ammonium formate/0.1M formic acid. The eluant was collected in scintillation counting tubes, followed by addition of 7ml of scintillation liquid. Mixing and counting concluded the operation.
The activities of the pyπolidine derivatives claimed in the formula I were assessed using the above described in vitro biological assay. Representative values for some example compoxmds are given in Table 3 below. The values refer to the capacity of the example compoxmds according to formula I to effectively antagonize oxytocin-induced IP3-synthesis mediated by the Oxytocin receptor. From the values shown in Table 3 it can be derived that said example test compounds according to formula I do exhibit a significant activity as Oxytocin receptor antagonists. Table 3
e) In vivo model for inhibtion of uterine contractions
Non-pregnant Charles River CD(SD) BR female rats (9-10 weeks old, 200-250g) were treated at 18 and 24 hours before the experiment with 250 μg/kg, i.p. diethylstilbestrol (DES). For the assay, the animal was anaesthetised by urethane (1.75 g/kg, i.p.) and placed on an homeothermic operating table. The trachea was isolated and cannulated with a suitable polyethylene (PE) tubing. A midline incision at the hypogastrium level was made and one uterine horn exposed, its cephalic end cannulated with a PE240 tubing and, after filling the internal cavity with 0.2 ml of sterile physiological saline, connected to a "Gemini" amplifying/recording system via a P23ID Gould Statham pressure transducer. For the i.v. route of administration of the test compoxmds, one jugular vein was isolated and cannulated with a PE60 tubing connected to a butterfly needle to allow the administration by a dispensing syringe. In the case of intraduodenal administration of the test compoxmds, the duodenum was isolated and similarly cannulated through a small incision in its wall. One carotid artery was also isolated and cannulated with PE60 catheter and connected to a suitable syringe for blood sample collection (see below). After a stabilization period, the same dose of oxytocin was repeatedly injected intravenously at 30-min intervals. When comparable contractile responses of the uterus to the selected dose of oxytocin were obtained, the dose of the test or reference compound was administered. Further injections of the same dose of oxytocin were then made for a suitable time after treatment to assess inhibitory effects of the compoxmds under study. The contractile response of the uterus to oxytocin was quantified by measuring the intrauterine pressure and the number of contractions. The effect of the reference and test compounds were evaluated by comparing pre- and post-treatment pressure values. In addition, at 2, 30, 90 and 210 minutes after test compoxmd administration, a 0.5-ml blood sample was withdrawn from the cannulated carotid artery of each experimental animal. Plasma was obtained by standard laboratory procedure and the resulting samples were stored at -20°C.
The activities of the pyrrolidine derivatives claimed in the formula I were assessed using the above described in vivo biological assay. Representative values for one example compoxmd are given in Table 4 below. The values refer to the capacity of the example compoxmd according to formula I to effectively antagonize oxytocin-induced uterine contractions in the rat. From the values shown in Table 4 it can be derived that said example test compoxmd according to formula I does exhibit a significant activity as tocolytic, i.e. uterine-relaxing, agent.
Table 4

Claims

Claims
1. Pyπolidine derivatives according to formula I
I
as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherem
X is selected from the group consisting of CR6R7, NOR6, NNR6R7;
A is selected from the group consisting of -(CO)-, -(C=O)-O-, -C(=NH)-, -(C=O)-NH-, - (OS)-NH, -SO2-, -SO2NH-, -CH2-,
B is either a group -(C=O)-NR8R9 or represents a heterocyclic residue having the formula
wherein Q is NR10, 0 or S; n is an integer selected of 0, 1 or 2;
Y, Z and E form together with the 2 carbons to which they are attached a 5-6 membered aryl or heteroaryl ring, R1 is selected from the group comprising or consisting of unsubstituted or substituted C-i- C6-alkyl, xmsubstituted or substituted C2-C6-alkenyl, xmsubstituted or substituted C2-C6- alkynyl, xmsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, xmsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, acyl, xmsubstituted or substituted Cι-C6-alkyl aryl, xmsubstituted or substituted Cι-C6-alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl group;
R2, R3, R4 and R5 are independently selected from each other from the group consisting of hydrogen, halogen, Ci-Cβ-alkyl, C]-C6-alkoxy;
R6 and R7 are independently selected from the group comprising or consisting of hydrogen, xmsubstituted or substituted -Cό alkyl, xmsubstituted or substituted C2-C6 * alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted alkoxy, xmsubstituted or substituted thioalkoxy, halogen, cyano, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, xmsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, xmsubstituted or substituted Cr C6-alkyl aryl, unsubstituted or substituted CrC6-alkyl heteroaryl;
R8, R9 and R10 are independently selected from the group comprising or consisting of hydrogen, xmsubstituted or substituted Cj-C alkyl, xmsubstituted or substituted C -C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl which may contain 1 to 3 heteroatoms selected of N, O, S, unsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, or
each pair R6, R7 and/or R8, R9 could form together with the N atom to which they are attached a 3-8 membered substituted or unsubstituted, saturated or unsaturated hetero- cyclic ring which may contain 1-2 further heteroatoms selected from N, S and O and which is optionally fused with an aryl, heteroaryl or 3-8 membered saturated or unsaturated cycloalkyl ring; R11 is selected from the group comprising or consisting of hydrogen, xmsubstituted or substituted Q-C.-alkyl, xmsubstituted or substituted alkenyl, unsubstituted or substi-tuted alkynyl, hydroxy, mercapto, alkoxy, thioalkoxy, aryl, heteroaryl, halogen, nitro, cyano, acyl, acyloxy, acylamino, aminocarbonyl, alkoxycarbonyl, sulfonyl, sulfoxy, carboxyl, primary, secondary or tertiary amino groups or quarternary ammonium moieties, unsubstituted or substituted saturated or xmsaturated 3-8-membered cyclo-alkyl,
with the proviso that if X is (=CH2), A is -(C=O)-O~, R1 is a t-butyl group, B could not be -(C=O)-NMe2, -(C=O)-NHMe, -(C=O)-NH-CH(Me)-(C=O)-NH-CH(Me)-COOH, - (C=O)-NH-CH(COOCH2-Ph)-CH2-COOPh;
with the further proviso that if X is (=CHR6) with R6 being cyclohexylmethyl, A is - (C=O)-O-, R1 is a t-butyl group, B could not be -(C=O)-NH-t-butyl;
with the further proviso that if X is a C1-C20 alkylidene, A is -(C=O)-O-, R1 is a t-butyl, B could not be
with R being C1-C12 alkyl and Hal being Cl, Br, J;
with the final proviso that if X is a -G20 alkylidene, A-R1 is a protective group, B could not be
with R being H or C1-C12 alkyl.
2. A pyπolidine derivative according to claim 1 , wherem B is a group -(C=O)-NHR9, in which R9 is selected from the group consisting of unsubstituted or substituted -C. alkyl, xmsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted saturated or xmsaturated 3-6-membered cycloalkyl which optionally contains a N atom, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, xmsubstituted or substituted Ci-C2-alkyl aryl, xmsubstituted or substituted C1-C -alkyl heteroaryl.
3. A pyπolidme derivative according to claim 1, wherein B is a fused heterocycle of the formula
4. A pyπolidine derivative accordmg to claim 2, wherein R9 is a heteroaryl selected from pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothia-zolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3 -oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzo-fxxryl, [2,3- dihydro]benzofuryl, isobenzofiiryl, benzothienyl, benzotriazolyl, isobenzo-thienyl, 2,1,3- benzothiadiazolyl, 2,1,3-benzoxadiazolyl, benzodioxolyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[l,2-a]ρyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, ρyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8- tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, acridinyl or benzoquinolyl and whereby said heteroaryl could be fused with a 3-8-membered cycloalkyl containing optionally 1-3 heteroatoms selected from N, O, S.
5. A pyrrolidine derivative accordmg to any of the preceding claims, wherein X is NOR6, and R6 is selected from the group consisting of H, unsubstituted or substituted Cι-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, xmsubstituted or substituted acyl, unsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, xmsubstituted or substituted saturated or unsaturated 3-8- membered cycloalkyl, xmsubstituted or substituted d-Cβ-alkyl aryl, xmsubstituted or substituted d-Cβ-alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups maybe fused with 1-2 further cycloalkyl or aryl or heteroaryl groups.
6. A pyπolidine derivative according to claim 5, wherein R6 is H, CH3, unsubstituted or substituted CH2-phenyl or allyl, preferably H or methyl.
7. A pyπolidine derivative according to any of the claims 1-4, wherein X is CHR6, R6 is selected from the group consisting of halogen, cyano, unsubstituted or substituted C3-C6 alkyl, xmsubstituted or substituted C2-C6 alkenyl, xmsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted alkoxy, unsubstituted or substituted thioalkoxy, nitro, acyl, alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted aryl, xmsubstituted or substituted heteroaryl, xmsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, xmsubstituted or substituted d-Cδ-alkyl aryl, xmsubstituted or substituted C-i- C6-alkyl heteroaryl, said cycloalkyl or aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl or aryl or heteroaryl groups.
8. A pyπolidine derivative accordmg to claim 7, wherein R6 is selected from the group consisting of halogen, cyano, C3-C6 alkyl or an xmsubstituted or substituted phenyl group.
9. A pyrrolidine derivative according to any of the preceding claims, wherem A is -(G=O)-, or -(C=O)-NH-, or -SO2-.
10. A pyrrolidine derivative according to claim 9, wherein A is -(C=O)-.
11. A pyπolidine derivative according to any of the preceding claims, wherem R1 is an d-Cβ- alkyl, C2-C6-alkenyl, unsubstituted or substituted C2-C6-alkynyl, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, Cι-C6-alkyl aryl, Q-Cό-alkyl heteroaryl.
12. A pyπolidine derivative accordmg to claim 11, wherein R1 is an Q-C6-alkyl or aryl group.
13. A pyπolidine derivative according to claim 12, wherein R1 is biphenyl.
14. A pyπolidme derivative accordmg to any of claims 1-4, wherein X is =NOR6 or =CHC1, R6 is a Cι-C6-alkyl or aryl or Ci-Cβ-alkyl aryl group, A is -(C=O)- and R1 is a Q-C.-alkyl or aryl or Cι-C6-alkyl aryl group.
15. A pyπolidine derivative according claim 14, wherein X is =NOR6, or =CHC1, R6 is methyl, B is an amido group of the formula -(C=O)NHR9, wherein R9 is an unsubstituted or substituted Ci-Cβ-alkyl aryl group, A is -(C=O)- and R1 is a biphenyl or an acetylmethyl group.
16. A pyπolidine derivative according claim 15, wherein X is =NOCH3, B is an amido group of the formula -(C=O)NHR9, wherein R9 is a substituted phenylethyl group, A is -(C=O)- and R1 is a substituted biphenyl.
17. A pyπolidine derivative according to any of the preceding claims selected from the following group:
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-(2-methoxyethyl)-4-(methoxyimino)-2- pyπolidinecarboxamide (2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-hydroxy-2-phenyl- ethyl)-2-pyπolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2- pyπolidinecarboxamide
(2S,4EZ)- 1-([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-
(methoxyimino)-2-pyπolidinecarboxamide
(3EZ,5S)-5-(lH-benzimidazol-2-yl)-l-([l,r-biphenyl]-4-ylcarbonyl)-3-pyπolidinone O- methyloxime
(2S,4EZ)- N-(2, 1 ,3 -benzothiadiazol-4-yl)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-4-(methoxy- imino)-2-pyrrolidinecarboxamide
(2S,4EZ)-1 -([ 1 , 1 ,-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinolmyl)-2- pyπolidinecarboxamide
(2S,4EZ)-l-acetoacetyl-N-benzyl-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-furylmethyl)-2- pyπolidinecarboxamide
(2S,4EZ)-l-[(4-chlorophenoxy)acetyl]-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2- hydroxy-2-phenethyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-allyl-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyπolidine- carboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(2-thienylmethyl)-2- pyrrolidinecarboxamide
(2S,4EZ)-4-(cyanomethylene)-N-(2-furylmethyl)-l-[(2-oxo-6-ρentyl-2H-pyran-3- yl)carbonyl]-2-pyπolidinecarboxamide (2S,4EZ)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-(methoxyimino)-2- pyrrolidinecarbόxamide
(2S,4EZ)-l-acetyl-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyπolidine- carboxamide
(2S,4EZ)-N-(2-furylmethyl)-4-(methoxyimino)- 1 -[(2-oxo-6-ρentyl-2H-ρyran-3-yl)- carbonyl] -2-pyπolidinecarboxamide
(2S,4EZ)-N-benzyl-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-methyl-2- pyπolidinecarboxamide
(2S,4EZ)-l-(diphenylacetyl)-4-(ethoxyimino)-N-(2-thienylmethyl)-2-pyπolidinecar- boxamide
(2S,4EZ)-N-(2,l,3-benzothiadiazol-4-yl)-4-(cyanomethylene)-l-(diρhenylacetyl)-2- pyrrolidinecarboxamide
(3EZ,5S)-5-(lH-benzimidazol-2-yl)-l-(diphenylacetyl)-3-pyπolidinone O-methyloxime
(2S)-2-[ 1 -([1,1 '-biphenyl]-4-ylcarbonyl)-4-methylene-2-pyπolidinyl]- IH-benzimidazole
(2S,4EZ)-1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-methoxyethyl)-2- pyπolidinecarboxamide
(3EZ,5S)-5-(lH-benzimidazol-2-yl)-l-(diphenylacetyl)-3-pyπolidinone O-allyloxime
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-[2-(diethylamino)ethyl]-4-(methoxyimino)- 2-pyπolidinecarboxamide
(2S,4EZ)-l-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-N-(2-thienylmethyl)-2- pyπolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-(3,4-dimethoxybenzyl)-4-(methoxyimino)-2- pyπolidinecarboxamide (2S,4EZ)-l-acetoacetyl-4-(methoxyimino)-N-(l-naphthylmethyl)-2-ρyπolidinecarbox- amide
(2S,4EZ)-N-allyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-l-(diphenylacetyl)-2- pyπolidinecarboxamide
(2S,4EZ)-4- {[(3 ,4-dichlorobenzyl)oxy]imino} -N1 -pentyl-N2-(6-quinolinyl)- 1 ,2-pyπoli- dinedicarboxamide
(2S,4EZ)-4-(chloromethylene)-l-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-2- pyπolidinecarboxamide
(2S)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-methylene-2- pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(6-quinolinyl)-2- pyπolidinecarboxamide
(2S,4EZ)-4-benzylidene-N-[2-(diethylamino)ethyl]-l-(diphenylacetyl)-2- pyπolidinecarboxamide
(2S,4EZ)-l-acetoacetyl-4-(methoxyimmo)-N-(2-thienylmethyl)-2-pyπolidinecarboxamide
(2S,4EZ)-l-acetyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[(2RS)-2-hydroxy-2-ρhenethyl]- 2-pyπolidinecarboxamide
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N1-(3,5-dichlorophenyl)-N2-(6-quinolinyl)- 1 ,2-pyπolidinedicarboxamide
(2S,4EZ)-4-(methoxyimino)-N-(l -naphthylmethyl)-l -(phenoxyacetyl)-2- pyπolidinecarboxamide
(2S,4EZ)-4-(chloromethylene)-N-(3,4-dimethoxybenzyl)-l-[(2-oxo-6-ρentyl-2H-pyran-3- yl)carbonyl]-2-pyπolidmecarboxamide (2S,4EZ)-l-(diphenylacexyl)-4-(memoxyimino)-N-(2-thienylmethyl)-2-pyπolidinecar- boxamide
(2S,4EZ)-N-benzyl-l-(diphenylacetyl)-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-[2- (diethylamino)ethyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]immo}-l-[4-(dimethylamino)butanoyl]-N-(6- quinolinyl)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-(5-ethyl-l,3,4-thiadiazol-2-yl)-4- (methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-benzyl- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-4-(methoxyimino)-2- pyπolidinecarboxamide
(2S,4EZ)-N-benzyl-l-(diphenylacetyl)-4-(ethoxyimino)-2-pyπolidmecarboxamide
(2S,4EZ)-N2-cycloρropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N1-(3-methoxyphenyl)-l,2- pyπolidinedicarboxamide
(2S,4EZ)-l-(diphenylacetyl)-N-[(2RS)-2-hydroxy-2-phenethyl]-4-{[(4- methoxybenzyl)oxy]-imino}-2 -pyrrolidinecarboxamide
(2__^-N-(2-furylmethyl)-4-methylene-l-[(2-oxo-6-pentyl-2H-pyran-3-yl)carbonyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-N-(2,l,3-benzothiadiazol-4-yl)-l-(diρhenylacetyl)-4-(methoxyimino)-2- pyπolidinecarboxamide
(2S,4EZ)-N-benzyl-l-(diphenylacetyl)-4-{[(4-methoxybenzyl)oxy]imino}-2- pyπolidinecarboxamide (2S,4EZ)-l-benzoyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-N-(6-quinolinyl)-2- pyπolidinecarboxamide
(2S,4EZ)- 1 -acetoacetyl-N-cyclopropyl-4- { [(3 ,4-dichlorobenzyl)oxy]imino } -2- pyπolidinecarboxamide
(2S,4EZ)-4-{[(3,4-dichlorobenzyl)oxy]imino}-N -[(2RS)-2-hydroxy-2-phenethyl]-N1- pentyl- 1 ,2-pyπolidmedicarboxamide
(2S,4EZ)-4-[(benzyloxy)imino]-N-(l-naphthylmethyl)-l-(phenoxyacetyl)-2- pyπolidinecarboxamide
(2S)- 1 -([ 1 , 1 '-biphenyl] -4-ylcarbonyl)-4-methylene-N-(6-quinolinyl)-2-pyπolidinecar- boxamide
(2S,4EZ)-N-cyclopropyl-4-{[(3,4-dichlorobenzyl)oxy]imino}-l-(diphenylacetyl)-2- pyπolidinecarboxamide
(2S,4EZ)- 1 -(4-cyanobenzoyl)-4- { [(3,4-dichlorobenzyl)oxy]imino} -N-(6-quinolinyl)-2- pyπolidinecarboxamide
(2S,4EZ)-N-cyclopropyl-4- {[(3,4-dichlorobenzyl)oxy]imino} - 1 -(methoxyacetyl)-2- pyπolidinecarboxamide
(2S,4EZ)-N-(l,3-benzodioxol-5-ylmethyl)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-4- (methoxyimino)-2-pyrrolidinecarboxamide
(3EZ,5S)-5-[(4-acetyl-l-piperazinyl)carbonyl]-l-acryloyl-3-pyrrolidinone O-(3,4- dichlorobenzyl)oxime
(2S)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-(2-furylmethyl)-4-methylene-2-pyrrolidinecar- boxamide (2S,4EZ)-4-(cyanomethylene)-N-(3,4-dimethoxybenzyl)-l-[(2-oxo-6-pentyl-2H-pyran-3- yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'- biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-3-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-
(methoxyimino)-2-pyπolidmecarbox£_mide
(2S,4EZ)-l-(4-benzoylbenzoyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2- pyπolidinecarboxamide
(2S,4EZ)-N-[(2i?S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-(3-phenoxybenzoyl)- 2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2i?_S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-(2-ρhenoxybenzoyl)- 2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l -[(2'-methyl[ 1,1'- biphenylj-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'- biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)- 1 -[(2'-methyl[ 1 , 1 *-biphenyl]-4- yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-(2-hydroxyethyl)-4-(methoxyimino)-N-methyl-l-[(2'-methyl[l,l'-biphenyl]-4- yl)carbonyl] -2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(lS,2S,3R,4R)-3- (hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2-pyπolidinecarboxamide (2S,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-(trαn5'-4-hydroxycyclohexyl)-4- (methoxyimino)-2-pyπolidmecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(lR,2R)-2-(hydroxymethyl)cyclohexyl]-4- (methoxyimino)-2-pyπolidmecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-phenoxyproρyl]-4-
(methoxyimmo)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-ρhenoxypropyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2i?S)-2-hydroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(l-hydroxycyclohexyl)methyl]-4-
(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(l-hydroxycyclohexyl)methyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylsulfonyl)-N-[(l -hydroxycyclohexyl)methyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-(3,4-dihydroxyphenyl)-2- hydroxyethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide (2S,4EZ)-N-[(2S)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)-l-[4-(4- pyridmyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[4-(2- pyridmyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2,3-dihydroxypropyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-3-(4- methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-(4-methoxyρhenoxy)ρropyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)ber_zoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(2i?S)-2-hydroxy-3-(4- methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,r-biρhenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxyproρyl]-4-(methoxyimino)- 2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)- 2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-4- (methoxyimino)-2-pyπolidinecarboxamide (2S,4EZ)- 1 -([1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitroρhenyl)ethyl]-4-(methoxyimino)-l-[4-(4- pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitroρhenyl)ethyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4-(methoxyimino)-l-[4-(2- pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l*-biρhenyl]-4-ylsulfonyl)-N-[(2RS)-2-hydroxy-2-(4-nitrophenyl)ethyl]-4- (memoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N- {(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxyρropyl} -1 -([1 , 1 '-biphenyl] -4- ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(methoxyimino)-l- [4-(4-pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N- {(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxypropyl} -4-(methoxyimino)- 1 -
[4-(3-pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-{(2RS)-3-[4-(acetylamino)phenoxy]-2-hydroxyproρyl}-l-([l,l'-biphenyl]-4- ylsulfonyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyπolidmecarboxamide
(2S,4EZ)-N-[(2i?)-2-hydroxy-2-phenylethyl]-4-(memoxyimino)-l-[4-(4- pyridinyl)benzoyl]-2-pyπolidinecarboxamide (2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[4-(3- pyridinyl)benzoyl]-2-ρyrroli dinecarboxamide
(2S,4EZ)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[4-(2- pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-
(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2- pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biρhenyl]-4-ylsulfonyl)-N-(3-hydroxypropyl)-4-(methoxyimino)-2- pyπolidinecarboxamide
(3EZ,5S)-l-([l,l'-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-4-phenyl-l- ρiρeridinyl)carbonyl]-3-pyπolidinone O-methyloxime
(3EZ,5S)-5-[(4-hydroxy-4-phenyl-l-piperidinyl)carbonyl]-l-[4-(4-pyridinyl)benzoyl]-3- pyπolidinone O-methyloxime
(3EZ,5S)-5 - [(4-hydroxy-4-phenyl- 1 -piperidinyl)carbonyl] - 1 -[4-(3-pyridinyl)benzoyl] -3 - pyπolidinone O-methyloxime
(3EZ,5S)-l-([l,l*-biphenyl]-4-ylsulfonyl)-5-[(4-hydroxy-4-phenyl-l- piperidinyl)carbonyl]-3-pyπolidinone O-methyloxime
(2S,4EZ)-l-([l,l*-biphenyl]-4-ylcarbonyl)-N-[(lS,2S)-2-hydroxycyclohexyl]-4- (methoxyimino)-2 -pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(lS,2S)-2-hydroxycyclohexyl]-4- (methoxyimino)-2-pyπolidinecarboxamide (2S,4EZ)-N-benzyl-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4- (methoxyimino)-2 -pyπolidinecarboxamide
(2S,4EZ)-N-benzyl-N-(2-hydroxyethyl)-4-(methoxyimino)-l-[4-(3-pyridinyl)benzoyl]-2- pyπolidinecarboxamide
(3EZ,5S)- 1 -([ 1 , 1 '-biρhenyl]-4-ylcarbonyl)-5- { [(3i?S)-3-hydroxypiperidinyl]carbonyl) -3- pyrrolidinone O-methyloxime
(3EZ,5S)-5-{[(3i?S)-3-hydroxypiperidinyl]carbonyl}-l-[4-(4-pyridinyl)benzoyl]-3- pyπolidinone O-methyloxime
(3EZ,5-S)-5-{[(3ΛS)-3-hydroxypiperidinyl]carbonyl}-l-[4-(3-pyridinyl)benzoyl]-3- pyπolidinone O-methyloxime
(3EZ,5S)-l-([l,l'-biρhenyl]-4-ylsulfonyl)-5-{[(3i-S)-3-hydroxypiperidinyl]carbonyl}-3- pyπolidinone O-methyloxime
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2- phenylethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-ρhenylethyl]-4-(methoxyimino)-l-
[4-(4-pyridinyl)benzoyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-ρhenylethyl]-4-(methoxyimino)-l- [4-(3-pyridinyl)benzoyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylsulfonyl)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2- phenylethyl] -4-(methoxyimino)-2 -pyπolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide (2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-l-[4-(4-pyridinyl)benzoyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-4-(methoxyimino)-l-[4-(3-pyridinyl)benzoyl]-2- pyπolidinecarboxamide
(2S,4EZ)-N-(2-a_ ilinoethyl)-4-(methoxyimino)-l-[4-(2-pyridinyl)benzoyl]-2- pyπolidinecarboxamide
(2S,4EZ)-N-(2-anilinoethyl)-l-([l,r-biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2- pyπolidinecarboxamide
(3EZ,5S)-l-([l,r-biphenyl]-4-ylcarbonyl)-5-[(4-hydroxy-l-ρiperidinyl)carbonyl]-3- pyπolidinone O-methyloxime
(3EZ,5S)-l-([l,l'-biρhenyl]-4-ylsulfonyl)-5-[(4-hydroxy-l-piperidinyl)carbonyl]-3- pyπolidinone O-methyloxime
(2S,4EZ)-N-[(lS,2R,3S,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-l-([l,r- biphenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-ρyπolidinecarboxamide
(2S,4EZ)-N-(3-amino-3-oxopropyl)-l-([l,r-biρhenyl]-4-ylcarbonyl)-4-(methoxyimino)-2- pyπolidinecarboxamide
(2S,4EZ)-N-[(lS,2S,3i?,4i?)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-l-([l,l'- biρhenyl]-4-ylsulfonyl)-4-(methoxyimino)-2-pyπoli dinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2- pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-(4-hydroxybutyl)-4-(methoxyimino)-2- pyπolidinecarboxamide (2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(lR,2R)-2-(hydroxymethyl)cyclohexyl]-4- (methoxyimmo)-2-ρyrrolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylsulfonyl)-N-[(lR,2S,3R,4S)-3- (hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-4-(methoxyimino)-2 -pyrrolidinecarboxamide
(2S,4EZ)-l-([l,l*-biphenyl]-4-ylsulfonyl)-N-[(lR,2»S)-2-(hydroxymethyl)cyclohexyl]-4-
(methoxyimino)-2-pyπolidinecarboxamide
(2S,4E and 4Z)-N-[(2i?S)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4E and 4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4E and 4Z)-N-[(2R)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l -[(2'-methyl[ 1,1'- biphenyl] -4-yl)carbonyl] -2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(lΛ,2S)-2-(hydroxymethyl)cyclohexyl]-4- (methoxyimino)-2 -pyπolidinecarboxamide
(2S,4EZ)-l-([l,r-biρhenyl]-4-ylcarbonyl)-N-[2-hydroxy-l-(hydroxymethyl)ethyl]-4-
(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(lS,2R,3S,4Λ)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-l-([l5l'- biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(lS,2S,3R,4R)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-l-([l,l'- biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyπolidinecarboxamide
(2SAEZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyπolidinecarboxamide (2ΛS)-3-({[(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyπolidinyl]- carbonyl} amino)-2-hydroxypropanoic acid
(2S,4EZ)-N-[(lΛ,2S)-2-(aminocarbonyl)cyclohexyl]-l-([l,r-biphenyl]-4-ylcarbonyl)-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(li?S)-2-hydroxy-l-methylethyl]-4-
(methoxyimino)-2 -pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-(4- nitrophenyl)ethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
4-({[(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyπolidinyl]- carbonyl} amino)butanoic acid
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-l-[(2'-methoxy[l,r-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyπolidmecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(2-naphthyl)ethyl]-l-[(2'-methoxy[l,r-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-ρyπolidinecarboxamide
(2S,4EZ)-N-[(lRS)-2-hydroxy-l-methylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2Ss4EZ)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-(4-nitroρhenyl)ethyl]-4- (methoxyimino)- 1 -[(2'-methyl[ 1 , 1 '-biphenyl] -4-yl)carbonyl] -2-ρyπolidinecarboxamide
(2S,4EZ)-N-[(lS,2S)-2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]-4- (methoxyimino)-l-[(2'-methoxy[l,r-biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(3EZ,5S)-5-[(4-hydroxy-l -piperidinyl)carbonyl]-l -[(2'-methyl[ 1 , 1 '-biphenyl]-4- yl)carbonyl] -3 -pyrrohdinone O-methyloxime (2S,4E_ζ)-N-[(lS,2S,3i?,4i?)-3-(aminocarbonyl)bicyclo[2.2.1]hept-5-en-2-yl]-4- (methoxyimino)-l -[(2'-methyl[ 1 , 1 '-biρhenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2i?S)-2-hydroxy-2-phenylethyl3-l-[(2'-methoxy[l,r-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxypropyl]-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]-4- yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2,3-dihydroxyproρyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'-biphenyl]- 4-yl)carbonyl]-2-ρyπolidinecarboxamide
(2S,4EZ)-N-(3-hydroxypropyl)-4-(methoxyimmo)- 1 -[(2'-methyl[ 1 , 1 '-biρhenyl]-4- yl)carbonyl] -2-pyπolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-l-([l,r-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2- pyrrolidinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-4-(methoxyimino)-l-[(2'-methyl[l,r-biphenyl]-4- yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-(3- hydroxyphenyl)ethyl]-4-(methoxyimmo)-2 -pyπolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-[(lS,2R,3S,4R)-3- (hydroxymethyl)bicyclo [2.2.1 ]hept-2-yl] -4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(lR,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-l-[(2'- methoxy[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
(2S,4EZ)-N-(trα«5-4-hydroxycyclohexyl)- 1 -[(2'-methoxy[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyπolidinecarboxamide (2S,4EZ)-N-[(lR,2R)-2-(hydroxymethyl)cyclohexyl]-l-[(2'-methoxy[l,r-biρhenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyπolidmecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-3-phenoxypropyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2'- ethyl [1,1 '-biphenyl] -4-yl)carbonyl] -2 -pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2'- methoxy[ 1 ,1 '-biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2i?S)-2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]-l-[(2'-methyl[l,l'- biphenyl] -4-yl)carbonyl] -4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2i?S)-2-hydroxy-2-(4-hydroxy-3 -methoxyρhenyl)ethyl]-l -[(2'-methoxy[ 1,1'- biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2.RS)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-l-[(2'-methoxy[l,r- biphenyl]-4-yl)carbonyl]-4-(methoxyimino)-2 -pyrrolidinecarboxamide
(2R,4EZ)-l-([l,l'-biρhenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-
(methoxyimino)-2-pyπolidinecarboxamide
(2R,4EZ)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)- l-[(2'-methyl[ 1,1'- biρhenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-[(2'-cyano[l,l'-biphenyl]-4-yl)carbonyl]-N-[(2i?S)-2-hydroxy-2-ρhenylethyl]- 4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-[(3',4'-dichloro[l,r-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2- phenylethyl]-4-(methoxyimmo)-2-pyπolidinecarboxamide (2S,4EZ)-l-[(2',6'-dimethyl[l,l*-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2- phenylethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-1 -[(2' ,3-dimethyl[l , 1 '-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2- ρhenylethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(27?S)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2'- methyl[l, -biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2'- cyano [1,1 '-biphenyl] -4-yl)carbonyl] -2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(3',4'- dichloro[l ,r-biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2i-S)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimino)-l-[(2',6'- dimethyl[ 1 , 1 '-biphenyl] -4-yl)carbonyl] -2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2RS)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]-4-(methoxyimmo)-l-[(2',3- dimethyl[ 1 , 1 '-biphenyl] -4-yl)carbonyl] -2-pyπolidinecarboxamide
(2S,4EZ)-l-[(3',4'-dichloro[l,r-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimmo)-2-pyπolidinecarboxamide
(2S,4EZ)-l-[(2',6'-dimethyl[l,l*-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-[(2',3-dimethyl[l,r-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-2-(4- hydroxyphenyl)ethyl]-4-(methoxyimino)-2-p τrolidinecarboxamide
(2S,4EZ)- 1 -[(2',6'-dimethyl[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4- methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyπolidinecarboxamide (2S,4EZ)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[(2RS)-2-hydroxy-3-(4- methoxyphenoxy)propyl]-4-(methoxyimino)-2-pyπolidmecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-l-[(2',6'-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyπoUdinecarboxamide
(2S,4EZ)-N-(2-amino-2-oxoethyl)-l-[(2',3-dimethyl[l,l'-biρhenyl]-4-yl)carbonyl]-4-
(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-(3-amino-3-oxoρroρyl)-l-[(2',6'-dimethyl[l,r-biρhenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-(3-amino-3-oxopropyl)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-1 -[(2',6'-dimethyl[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy- 1 - (hydroxymethyl)ethyl]-4-(methoxyimino)-2-ρyπolidmecarboxamide
(2S,4EZ)-1 -[(2',3-dimethyl[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-N-[2-hydroxy- 1 - (hydroxymethyl)ethyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-[(2'-cyano[l,l'-biphenyl]-4-yl)carbonyl]-N-[(lR,2i?)-2-
(hydroxymethyl)cyclohexyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(3EZ,5S)-5-(3,4-dihydro-2(lH)-isoquinolinylcarbonyl)-l-[(2',3-dimethyl[l,r-biphenyl]-4- yl)carbonyl]-3-pyrrolidinone O-methyloxime
(2SJ4EZ)-N-[(lR)-2-hydroxy-l-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-l-[(2*,6'-dimethyl[l,r-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]- 4-(methoxyimino)-2-pyπolidinecarboxamide (2S,4EZ)-l-[(2',3-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-N-[2-(4-hydroxyphenyl)ethyl]- 4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-l-[(2',6'-dimethyl[l,l*-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]- 4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-1 -[(2',3-dimethyl[ 1 ,1 '-biphenyl]-4-yl)carbonyl]-N-[2-(3-hydroxyphenyl)ethyl]-
4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-1 -[(2',3-dimethyl[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-N-[(li-,2S)-2-hydroxy-l ,2- diphenylethyl]-4-(methoxyimino)-2-ρyπolidinecarboxamide
(2RS)-2-[( {(2S,4EZ)-4-(methoxyimino)-l -[(2'-methyl[l , 1 '-biphenyl] -4- yl)carbonyl]pyπolidinyl}carbonyl)amino]-3-phenylpropanoic acid
(2S,4E )-N-[(li?,2S)-2-(aminocarbonyl)cyclohexyl]-l-[(2',6'-dimethyl[l,l'-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(lJ?,2S)-2-(ammocarbonyl)cyclohexyl]-l-[(2',3-dimethyl[l,r-biphenyl]-4- yl)carbonyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide
4'-{[(2S,4EZ)-2-{[4-(2-hydroxyethyl)-l-piperazinyl]carbonyl}-4-
(methoxyimino)pyrrolidinyl] carbonyl} [1,1 '-biphenyl] -2-carbonitrile
(3EZ,5S)-l-[(3',4'-dichloro[l,l'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-l- piperazinyl]carbonyl} -3 -pyπolidinone O-methyloxime
(3EZ,5S)-l-[(2',6'-dimethyl[l,l'-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-l- piperazinyl]carbonyl}-3-pyπolidinone O-methyloxime
(3EZ,5S)-l-[(2',3-dimethyl[l,r-biphenyl]-4-yl)carbonyl]-5-{[4-(2-hydroxyethyl)-l- piperazinyl]carbonyl} -3 -pyπolidinone O-methyloxime (3EZ,5S)-l-[(2'-methyl[l,r-biρhenyl]-4-yl)carbonyl]-5-({4-[4-(trifluoromethyl)phenyl]-l- piperazinyl} carbonyl)-3 -pyπolidinone O-methyloxime
(3EZ,5S)- 1 -[(2'-methyl[ 1 , 1 '-biphenyl]-4-yl)carbonyl]-5-( {4-[3-(trifluoromethyl)phenyl]-l- piperazinyl} carbonyl)-3-pyπolidinone O-methyloxime
(2S,4EZ)-4-(methoxyimino)-l -[(2'-methyl[ 1 ,1 '-biphenyl]-4-yl)carbonyl]-2- pyrrolidinecarboxamide
(2S,4EZ)-4-(methoxyimino)-N-methyl- 1 -[(2'-methyl[ 1 , 1 '-biρhenyl]-4-yl)carbonyl]-2- pyπolidinecarboxamide
(2S,4EZ)-4-(methoxyimino)-N^'-dimethyl-l-[(2'-methyl[l,r-biρhenyl]-4-yl)carbonyl]-2- pyπolidinecarboxamide
(2S,4EZ)-N-[(3i-)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'- biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4-(methoxyimino)-l-[(2'-methyl[l,l'- biphenyl] -4-yl)carbonyl] -2-pyπolidinecarboxamide
(2S,4EZ)-l-([l,r-biphenyl]-4-ylcarbonyl)-N-[(3R)-3-hydroxy-3-phenylpropyl]-4-
(methoxyimino)-2 -pyπolidinecarboxamide
(2S,4EZ)- 1 -([ 1 , 1 '-biphenyl]-4-ylcarbonyl)-N-[(3S)-3-hydroxy-3-phenylpropyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-{[2'- (trifluoromethyl)[ 1 , 1 '-biphenyl] -4-yl] carbonyl} -2-pyrrolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-{[2'-chloro[l,l'- biphenyl]-4-yl]carbonyl}-2-pyπolidinecarboxamide (2S,4EZ)-N-(2-hydroxyphenyl)-4-(methoxyimino)-l-[(2'-methyl[l,l'-biρhenyl]-4- yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[2-(hydroxymethyl)phenyl]-4-(methoxyimino)-l -[(2'-methyl[l , 1 '-biphenyl]- 4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4EZ)-N-[(2S)-2-hydroxy-2-ρhenylethyl]-4-(methoxyimino)-l-[(2-methyl[l,r- biphenyl]-4-yl)carbonyl]-2-pyπolidinecarboxamide
(2S,4E and 4Z)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2S)-2-hydroxy-2-phenylethyl]-4- (methoxyimino)-2-pyπolidinecarboxamide
(2S,4EZ)-4-(methoxyimino)-l-[(2'-methyl[l,l'-biphenyl]-4-yl)carbonyl]-N-(2- phenylethyl)-2-pyπolidinecarboxamide
18. A pyπolidine derivative according to any of the preceding claims selected from the following group:
(2S,4EZ)- 1 -([ 1 , 1 *-biphenyl]-4-ylcarbonyl)-4-(chloromethylene)-N-(2-hydroxy-2-ρhenyl- ethyl)-2-pyπolidinecarboxamide
(2S,4EZ)-l-([lJl'-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimmo)-2- pyπolidinecarboxamide
(2S,4EZ)-l-([l,l'-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-ρhenethyl]-4-(methoxy- imino)-2-pyrroli dinecarboxamide
(3EZ,5S)-5-(lH-benzimidazol-2-yl)-l-([l,l'-biphenyl]-4-ylcarbonyl)-3-ρyπolidinone O- methyloxime
(2S,4EZ)-N-(2,l,3-benzothiadiazol-4-yl)-l-([l,r-biρhenyl]-4-ylcarbonyl)-4-(methoxy- imino)-2-pyπolidinecarboxamide (2S,4EZ)- 1 -([ 1 , 1 ,-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-N-(6-quinolinyl)-2- pyrrolidinecarboxamide.
(2S,4Z)-Ν-[(2»S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2 -pyrrolidinecarboxamide
(2S,4E)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-l-[(2'-methyl[l,r- biphenyl]-4-yl)carbonyl]-2 -pyπolidinecarboxamide
19. A pyπolidine derivative according to any of claims 1 to 18 for use as a medicament.
20. Use of a pyπolidine derivatives according to any of claims 1 to 18 for the preparation of a pharmaceutical composition for the treatment and/or prevention of premature labor, premature birth and dysmenoπhea.
21. Use of a pyπolidme derivatives according to any of claims 1 to 18 for the preparation of a pharmaceutical composition for the modulation of the oxytocm receptor.
22. Use according to claim 21, wherein said modulation consists in the blocking of the oxytocin receptor or in antagonising the binding of oxytocm to its receptor.
23. Use accordmg to claim 22 for the treatment or prevention of disorders mediated by the oxytocin receptor.
24. Use of a pyπolidine derivative to any of claims 1 to 18 for the preparation of a pharmaceutical composition for oral administration.
25. A pharmaceutical composition containing at least one pyπolidine derivative accordmg to any of the claims 1 to 18 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
26. Process for the preparation of a pyrrolidine derivative according to any of claims 1 to 18,
wherein the following reaction is performed : la
whereby LG is a leaving group and the substituents R^R9, A and X are as above defined.
27. Process for the preparation of a pyrrolidine derivative accordmg to any of claims 1 to 18,
wherein the following reaction is performed :
XV *
whereby LG is a leaving group and the substituents R^R5, Rπ, A, E, Q, X, Y and Z are as above defined.
28. Process according to claim 27, wherein compoxmd XV is obtained as follows
XII! XIV
N-Deprotection
XV
EP01929439A 2000-03-27 2001-03-20 Pyrrolidine derivatives useful as bax inhibitors Expired - Lifetime EP1268419B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP01929439A EP1268419B1 (en) 2000-03-27 2001-03-20 Pyrrolidine derivatives useful as bax inhibitors
CY20061101060T CY1105519T1 (en) 2000-03-27 2006-07-28 PYRROLIDINE DERIVATIVES USEFUL AS BAX PROTEIN INHIBITORS

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP00106034 2000-03-27
EP00106034 2000-03-27
PCT/EP2001/003171 WO2001072705A1 (en) 2000-03-27 2001-03-20 Pharmaceutically active pyrrolidine derivatives as bax inhibitors
EP01929439A EP1268419B1 (en) 2000-03-27 2001-03-20 Pyrrolidine derivatives useful as bax inhibitors

Publications (2)

Publication Number Publication Date
EP1268419A1 true EP1268419A1 (en) 2003-01-02
EP1268419B1 EP1268419B1 (en) 2006-06-21

Family

ID=8168169

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01929439A Expired - Lifetime EP1268419B1 (en) 2000-03-27 2001-03-20 Pyrrolidine derivatives useful as bax inhibitors

Country Status (33)

Country Link
US (2) US7211601B2 (en)
EP (1) EP1268419B1 (en)
JP (2) JP2003528854A (en)
KR (1) KR100714585B1 (en)
CN (1) CN1296354C (en)
AR (1) AR029499A1 (en)
AT (1) ATE330940T1 (en)
AU (2) AU5620901A (en)
BG (1) BG107132A (en)
BR (1) BR0109900A (en)
CA (1) CA2401242A1 (en)
CY (1) CY1105519T1 (en)
CZ (1) CZ20023243A3 (en)
DE (1) DE60120940T2 (en)
DK (1) DK1268419T3 (en)
EA (1) EA006424B1 (en)
EE (1) EE200200555A (en)
ES (1) ES2261404T3 (en)
HK (1) HK1054031B (en)
HR (1) HRP20020705A2 (en)
HU (1) HUP0300994A2 (en)
IL (1) IL151912A0 (en)
MX (1) MXPA02009382A (en)
NO (1) NO323969B1 (en)
NZ (1) NZ521060A (en)
PL (1) PL358001A1 (en)
PT (1) PT1268419E (en)
SI (1) SI1268419T1 (en)
SK (1) SK13832002A3 (en)
UA (1) UA74362C2 (en)
WO (1) WO2001072705A1 (en)
YU (1) YU73502A (en)
ZA (1) ZA200206799B (en)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074769A1 (en) * 2000-03-27 2001-10-11 Applied Research Systems Ars Holding N.V. Pharmaceutically active pyrrolidine derivatives as bax inhibitors
BR0211030A (en) * 2001-06-18 2004-06-22 Applied Research Systems Pyrrolidine oxadiazole derivative, use of a pyrrolidine oxadiazole derivative, pharmaceutical composition containing at least one pyrrolidine oxadiazole derivative, method for preparing a pyrrolidine oxadiazole compound
AR034897A1 (en) 2001-08-07 2004-03-24 Hoffmann La Roche N-MONOACILATED DERIVATIVES OF O-PHENYLENDIAMINS, THEIR HETEROCICLICAL ANALOGS OF SIX MEMBERS AND THEIR USE AS PHARMACEUTICAL AGENTS
US7030141B2 (en) * 2001-11-29 2006-04-18 Christopher Franklin Bigge Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
US7405234B2 (en) 2002-05-17 2008-07-29 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
UA78058C2 (en) * 2002-07-05 2007-02-15 Applied Research Systems Pyrrolidine derivative as oxitocin antagonists
US7632858B2 (en) * 2002-11-15 2009-12-15 Bristol-Myers Squibb Company Open chain prolyl urea-related modulators of androgen receptor function
EP1597229B1 (en) * 2003-02-27 2009-11-18 Merck Serono SA Pyrrolidine derivatives as oxytocin antagonists
US7820702B2 (en) 2004-02-04 2010-10-26 Bristol-Myers Squibb Company Sulfonylpyrrolidine modulators of androgen receptor function and method
AU2005217153A1 (en) * 2004-02-26 2005-09-09 Merck Serono Sa Method for preparing pyrrolidine oximes
US7696241B2 (en) 2004-03-04 2010-04-13 Bristol-Myers Squibb Company Bicyclic compounds as modulators of androgen receptor function and method
US7625923B2 (en) 2004-03-04 2009-12-01 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function
CA2746943A1 (en) * 2008-12-18 2010-07-15 Boehringer Ingelheim International Gmbh Serotonin 5-ht2b receptor inhibitors
US9120776B2 (en) 2011-09-22 2015-09-01 Takeda Pharmaceutical Company Limited Condensed heterocyclic compound
EP2845850A1 (en) 2013-09-10 2015-03-11 ObsEva S.A. Pyrrolidine derivatives as oxytocin/vasopressin V1a receptors antagonists
EP2886107A1 (en) 2013-12-17 2015-06-24 ObsEva S.A. Oral formulations of pyrrolydine derivatives
EP3753921A1 (en) 2014-07-02 2020-12-23 ObsEva S.A. Crystalline (3z,5s)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one o-methyloxime useful in methods of treating conditions related to the ot-r activity
CN114621962B (en) * 2022-03-21 2024-05-14 广西大学 Peanut AhBI-1 gene VIGS silencing system
WO2024165071A1 (en) * 2023-02-09 2024-08-15 上海葆正医药科技有限公司 Imine compounds as well as preparation method therefor and use thereof
CN117044622A (en) * 2023-09-22 2023-11-14 贵州师范大学 Breeding mode of petal-free leaf mustard type rape

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL23907A (en) 1964-08-05 1971-05-26 Upjohn Co Lincomycin analogues and process for producing them
US3555007A (en) 1968-07-22 1971-01-12 Upjohn Co 7-deoxy-7-halo lincomycin d derivatives
US3674647A (en) 1970-10-07 1972-07-04 Upjohn Co Preparation of lincomycin analogues
US4596819A (en) * 1984-01-23 1986-06-24 Warner-Lambert Company Modified tripeptides
GB9316162D0 (en) 1993-08-04 1993-09-22 Zeneca Ltd Fungicides
EP0805681A4 (en) 1995-01-24 1998-05-06 Merck & Co Inc Tocolytic oxytocin receptor antagonists
US5756497A (en) 1996-03-01 1998-05-26 Merck & Co., Inc. Tocolytic oxytocin receptor antagonists
AR016133A1 (en) * 1997-07-31 2001-06-20 Wyeth Corp CARBAMILOXI COMPOUND INHIBITING THE ADHESION OF LEUKOCYTES THROUGH VLA-4, COMPOUNDS THAT ARE DRUGS OF THESE COMPOUNDS, PHARMACEUTICAL COMPOSITION, METHOD FOR SETTING VLA-4 TO A BIOLOGICAL SAMPLE, METHOD FOR THE TREATMENT OF A TREATMENT
US6329418B1 (en) 1998-04-14 2001-12-11 The Procter & Gamble Company Substituted pyrrolidine hydroxamate metalloprotease inhibitors
WO2000004005A1 (en) * 1998-07-14 2000-01-27 Ono Pharmaceutical Co., Ltd. Amino acid derivatives and drugs containing the same as the active ingredient
US6235755B1 (en) * 1998-08-07 2001-05-22 Applied Research Systems Ars Holding N.A. FSH mimetics for the treatment of infertility
SK10742001A3 (en) * 1999-01-27 2002-08-06 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors
AU759022B2 (en) * 1999-02-18 2003-04-03 Kaken Pharmaceutical Co., Ltd. Novel amide derivatives as growth hormone secretagogues
JP2002539192A (en) * 1999-03-15 2002-11-19 アクシス・ファーマシューティカルズ・インコーポレイテッド Novel compounds and compositions as protease inhibitors
ES2257296T3 (en) * 1999-05-05 2006-08-01 MERCK &amp; CO., INC. NEW PROLINES AS ANTIMICROBIAL AGENTS.
GB0000079D0 (en) * 2000-01-05 2000-02-23 Ferring Bv Novel antidiuretic agents
WO2001074769A1 (en) * 2000-03-27 2001-10-11 Applied Research Systems Ars Holding N.V. Pharmaceutically active pyrrolidine derivatives as bax inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0172705A1 *

Also Published As

Publication number Publication date
CY1105519T1 (en) 2010-07-28
US7211601B2 (en) 2007-05-01
ZA200206799B (en) 2003-08-26
IL151912A0 (en) 2003-04-10
NO323969B1 (en) 2007-07-23
DE60120940T2 (en) 2007-01-25
SI1268419T1 (en) 2006-10-31
ES2261404T3 (en) 2006-11-16
NZ521060A (en) 2004-05-28
NO20024598L (en) 2002-11-25
JP5580364B2 (en) 2014-08-27
DK1268419T3 (en) 2006-10-02
PT1268419E (en) 2006-08-31
CA2401242A1 (en) 2001-10-04
HK1054031B (en) 2007-05-04
MXPA02009382A (en) 2003-01-28
AU5620901A (en) 2001-10-08
UA74362C2 (en) 2005-12-15
DE60120940D1 (en) 2006-08-03
JP2012149098A (en) 2012-08-09
HK1054031A1 (en) 2003-11-14
JP2003528854A (en) 2003-09-30
CN1296354C (en) 2007-01-24
US20030212012A1 (en) 2003-11-13
CZ20023243A3 (en) 2003-01-15
AU2001256209B2 (en) 2006-02-16
BR0109900A (en) 2003-06-03
US20080167318A1 (en) 2008-07-10
EA006424B1 (en) 2005-12-29
EA200201026A1 (en) 2003-02-27
EP1268419B1 (en) 2006-06-21
SK13832002A3 (en) 2003-03-04
CN1419541A (en) 2003-05-21
HRP20020705A2 (en) 2004-12-31
PL358001A1 (en) 2004-08-09
WO2001072705A1 (en) 2001-10-04
AR029499A1 (en) 2003-07-02
ATE330940T1 (en) 2006-07-15
HUP0300994A2 (en) 2003-08-28
YU73502A (en) 2005-11-28
KR20020095195A (en) 2002-12-20
BG107132A (en) 2003-04-30
KR100714585B1 (en) 2007-05-07
NO20024598D0 (en) 2002-09-25
EE200200555A (en) 2004-06-15

Similar Documents

Publication Publication Date Title
JP5580364B2 (en) Pharmaceutically active pyrrolidine derivatives
AU2001256209A1 (en) Pharmaceutically active pyrrolidine derivatives
US20070129381A1 (en) Pharmaceutically active pyrrolidine ester derivatives
AU2001252222A1 (en) Pharmaceutically active pyrrolidine derivatives as bax inhibitors
WO2001074769A1 (en) Pharmaceutically active pyrrolidine derivatives as bax inhibitors
JP4511184B2 (en) Triazoles as oxytocin antagonists
JP4426284B2 (en) Pyrrolidine oxadiazole derivatives and thiadiazole derivatives
AU2002256685A1 (en) Pyrrolidine ester derivatives with oxytocin modulating acitvity
JP4773335B2 (en) Pyrrolidine derivatives as oxytocin antagonists
TW201546050A (en) Novel benzoazepine derivatives and medical applications thereof

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020925

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL PAYMENT 20020925;LT PAYMENT 20020925;LV PAYMENT 20020925;MK PAYMENT 20020925;RO PAYMENT 20020925;SI PAYMENT 20020925

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SCHEER, ALEXANDER

Inventor name: THOMAS, RUSSEL

Inventor name: QUATTROPANI, ANNA

Inventor name: HALAZY, SERGE

Inventor name: SCHWARZ, MATTHIAS

Inventor name: BAXTER, ANTHONY

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SCHWARZ, MATTHIAS

Inventor name: THOMAS, RUSSEL

Inventor name: SCHEER, ALEXANDER

Inventor name: HALAZY, SERGE

Inventor name: QUATTROPANI, ANNA

Inventor name: BAXTER, ANTHONY

17Q First examination report despatched

Effective date: 20041220

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20060621

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: SERONO INTERNATIONAL SA CORPORATE IP DEPARTMENT

REF Corresponds to:

Ref document number: 60120940

Country of ref document: DE

Date of ref document: 20060803

Kind code of ref document: P

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Effective date: 20060630

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20060402686

Country of ref document: GR

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2261404

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20070214

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MC

Payment date: 20070227

Year of fee payment: 7

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCAR

Free format text: MERCK SERONO INTERNATIONAL S.A. CORPORATE IP DEPARTMENT;9, CHEMIN DES MINES;1202 GENEVE (CH)

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20070313

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FI

Payment date: 20070314

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20070320

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20070326

Year of fee payment: 7

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20070322

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: LABORATOIRES SERONO SA

Free format text: APPLIED RESEARCH SYSTEMS ARS HOLDING N.V.#PIETERMAAI 15#CURACAO (AN) -TRANSFER TO- LABORATOIRES SERONO SA#CENTRE INDUSTRIEL#1267 COINSINS, VAUD (CH)

NLS Nl: assignments of ep-patents

Owner name: LABORATOIRES SERONO SA

Effective date: 20070920

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

BECA Be: change of holder's address

Owner name: S.A. LABORATOIRES SERENOCENTRE INDUSTRIEL, CH-1267

Effective date: 20060621

BECH Be: change of holder

Owner name: S.A. LABORATOIRES SERENO

Effective date: 20060621

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20070214

Year of fee payment: 7

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20080922

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20080320

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20080331

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060922

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20080922

LTIE Lt: invalidation of european patent or patent extension
LTLA Lt: lapse of european patent or patent extension

Effective date: 20080320

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20080320

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20080320

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20081128

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20090313

Year of fee payment: 9

Ref country code: DK

Payment date: 20090313

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20090303

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20090331

Year of fee payment: 9

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: MERCK SERONO SA

Free format text: LABORATOIRES SERONO SA#CENTRE INDUSTRIEL#1267 COINSINS, VAUD (CH) -TRANSFER TO- MERCK SERONO SA#CENTRE INDUSTRIEL#1267 COINSINS, VAUD (CH)

Ref country code: CH

Ref legal event code: NV

Representative=s name: MERCK SERONO S.A. - GENEVA

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20090306

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060621

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20090401

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20080320

BERE Be: lapsed

Owner name: S.A. LABORATOIRES SERENO

Effective date: 20100331

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20101001

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

EUG Se: european patent has lapsed
REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

REG Reference to a national code

Ref country code: FR

Ref legal event code: CD

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100320

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20101001

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100331

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100331

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100331

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 60120940

Country of ref document: DE

Owner name: MERCK SERONO SA, CH

Free format text: FORMER OWNER: LABORATOIRES SERONO S.A., COINSINS, CH

Effective date: 20110427

Ref country code: DE

Ref legal event code: R081

Ref document number: 60120940

Country of ref document: DE

Owner name: MERCK SERONO SA, COINSINS, CH

Free format text: FORMER OWNER: LABORATOIRES SERONO S.A., COINSINS, VAUD, CH

Effective date: 20110427

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: MERCK SERONO SA

Effective date: 20110901

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100321

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20150212

Year of fee payment: 15

Ref country code: DE

Payment date: 20150317

Year of fee payment: 15

Ref country code: IT

Payment date: 20150223

Year of fee payment: 15

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20150318

Year of fee payment: 15

Ref country code: FR

Payment date: 20150309

Year of fee payment: 15

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60120940

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20160320

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20161130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160320

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161001

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160320

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20170428

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160321